WO1981001145A1 - Hydrolytic enzyme-activatible pro-drugs - Google Patents
Hydrolytic enzyme-activatible pro-drugs Download PDFInfo
- Publication number
- WO1981001145A1 WO1981001145A1 PCT/US1980/001290 US8001290W WO8101145A1 WO 1981001145 A1 WO1981001145 A1 WO 1981001145A1 US 8001290 W US8001290 W US 8001290W WO 8101145 A1 WO8101145 A1 WO 8101145A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- drug
- moiety
- amino acid
- specifier
- acid residue
- Prior art date
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6891—Pre-targeting systems involving an antibody for targeting specific cells
- A61K47/6899—Antibody-Directed Enzyme Prodrug Therapy [ADEPT]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
- C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
- C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- This invention relates to hydrolytic enzyme- activatible pro-drugs and, in particular, to tumor- specific pro-drugs of antineoplastic agents which are selective substrates for drug-activating enzymatic cleavage by tumor-associated proteases.
- One approach to improving the efficiency of drug action and the selectivity of drug delivery is to prepare a reversible derivative of a drug which is itself pharmacologically inactive, but which becomes activated in vivo to liberate the parent drug, typically, but not necessarily, by enzymatic attack.
- a drug derivative of this type can be tailored to overcome certain undesirable properties of the parent drug, such as, for example, bitterness or tartness, offensive odor, gastric or intestinal upset and irritation, pain on injection, lack of absorption, slow or rapid metabolism, or lack of stability in the bulk state, the dosage form, or in vivo; or it can be designed to be activated selectively at the site of intended action, so that undesired effects can be lessened,
- the present invention is primarily concerned with pro-drugs of this latter type, which are selectively activatible at the site of intended action, and, in particular, to pro-drugs of antineoplastic agents which are selectively activatible at the tumor site.
- pro-drugs of this latter type which are selectively activatible at the site of intended action
- pro-drugs of antineoplastic agents which are selectively activatible at the tumor site.
- One aspect of the present invention is more broadly applicable to pro-drugs in general, as will become more readily apparent hereinbelow.
- antineoplastic agents currently being used in cancer chemotherapy rely for their effectiveness on being selectively cytotoxic to rapidly proliferating cells.
- certain normal cells are also rapidly proliferating, such as, for example, bone marrow and spleen cells.
- bone marrow and spleen toxicity are often limiting factors in the effectiveness of such antineoplastic agents in cancer chemotherapy.
- One approach in trying to overcome this problem is to design a pro-drug of the antineoplastic agent which will be selectively activatible at the tumor-site, for example, by being a selective substrate for drug-activating enzymatic cleavage by a tumor-associated enzyme.
- pro-drug of this type In order for a pro-drug of this type to be useful in cancer chemotherapy, there are several criteria which it must meet. First of all, there must be enough of the activating enzyme in the tumor to generate cytotoxic levels of free drug in the vicinity of the tumor. Secondly, there must be means available to minimize activation of the pro-drug at sites distant from the tumor, and to mitigate the effects of such activation if it occurs. This criterion is clearly related to the first one, since it is the relative amount of tumor-associated and extra-tumor enzymatic activity which is critical for selectivity. Thirdly, the pro-drug must be a suitable substrate for the tumor-associated enzyme under physiological conditions and a poor substrate for other enzymes.
- the pro-drug must be considerably less toxic than the activated drug, i ⁇ .e., at least on the order of ten times less active and preferably on the order of a hundred or a thousand times less active.
- the activated species must have a reasonably short biological half-life so that the toxic effects of the locally activated drug are limited to the tumor and selectivity is not lost by diffusion of the drug away from the site of activation.
- hy drolytic enzyme-activatible pro-drugs in general, is the problem sometimes posed by the nature of the drug molecule being derivatized. If the drug molecule is large or has pronounced polar or apolar character, steric or electronic factors at the intended cleavage site could interfere with the enzymatic cleavage reaction and thereby prevent the pro-drug from being a suitable substrate for the target enzyme.
- plasmin and plasminogen activator are proteases with trypsin-like specificity in the sense that they both cleave next to basic amino acids. Substantial information exists concerning the specificity of plasmin and plasminogen activator, based on the use of artificial substrates as well as analysis of the peptide bonds cleaved in the natural substrate.
- Plasminogen activator shows considerable substrate specificity towards its natural substrate, plasminogen, in which a single Arg-Val bond is cleaved in converting plasminogen to plasmin.
- Plasmin is often regarded as a rather unspecific, trypsin-like protease. However, it cleaves a limited number of bonds in dissolving a fibrin clot. Examination of the plasmin cleavage sites in its natural substrate, fibrin, reveal that eleven of the fifteen earliest cleavages are at lysine residues, and in fifteen of the twenty earliest cleavages (including all of the earliest nine cleavages) a hydropho amino acid precedes the lysine or arginine. Hence, the implication is that plasmin is selective for lysine residues preceded by a hydrophobic amino acid residue.
- Another object of the invention is to provide a tumor-specific pro-drug of an antineoplastic agent in accordance with the preceding object, which is a highly selective substrate for drug-activating enzymatic cleavage by one or more tumor-associated hydrolytic enzymes.
- a further object of the invention is to provide a tumor-specific pro-drug of an antineoplastic agent in accordance with the preceding objects, wherein the activating enzyme is one which is present in the tumor in sufficient amounts to generate cytotoxic levels of free drug in the vicinity of the tumor.
- Still another object of the invention is to provide a tumor-specific pro-drug of an antineoplastic agent in accordance with the preceding objects, wherein the activating enzyme is one whose presence at sites distant from the tumor is insufficient to generate cytotoxic levels of free drug in the vicinity of such distant sites.
- a still further object of the present invention is to provide a tumor-specific pro-drug of an antineoplastic agent in accordance with the preceding objects, which is considerably less toxic than the activated drug.
- Yet another object of the present invention is to provide a tumor-specific pro-drug of an antineoplastic agent in accordance with the preceding objects, wherein the activated drug has a reasonably short biological half-life so that the cytotoxic ef- fects of the locally activated drug are limited to the tumor and selectivity is not lost by diffusion of the drug away from the site of activation.
- a yet further object of the present invention is to provide hydrolytic enzyme-activatible pro- drugs, including those of the type set forth in the preceding objects, which include connector means for spacing the drug-activating enzymatic cleavage site sufficiently far away from the drug molecule so as to prevent steric and/or electronic interference with the enzymatic cleavage reaction, which connector means does not in itself prevent release of the free drug in pharmacologically active form following the enzymatic cleavage reaction.
- antineoplastic agent with a peptide specifier at a reactive site appropriate for inhibiting the pharmacological activity of the antineoplastic agent, to thereby convert the antineoplastic agent into a pharmacologically inactive peptidyl derivative pro- drug.
- the peptide specifier has an amino acid residue sequence specifically tailored so as to render the peptidyl derivative a selective substrate for drug-activating enzymatic cleavage by one or more tumor-associated fibrinolytic and/or blood-coagulating proteases, such as plasmin and plasminogen activator.
- the enzymatic cleavage reaction will remove the peptide specifier moiety from the pro-drug and effect release of the antineoplastic agent in pharmacologically active form selectively at the tumor site.
- peptidyl derivative pro-drug with its peptide specifier moiety and its antineoplastic agent moiety covalently linked together through an intermediate self-immolative connector moiety having a molecular structure such that enzymatic cleavage of the bond covalently linking it to the peptide specifier moiety will initiate spontaneous cleavage of the bond covalently linking it to the antineoplastic agent moiety to thereby effect release of the antineoplastic agent in pharmacologically active form.
- the intermediate self- immolative connector aspect of the present invention is not limited in its application to protease-activatible pro-drugs of antineoplastic agents, but is equally applicable to a variety of other types of hydrolytic enzyme-activatible pro-drugs wherein steric and/or electronic hindrance by the drug molecule might otherwise interfere with the drug-activating enzymatic cleavage reaction.
- the self-immolative connector aspect of the present invention may also be used to impart to the pro-drugs greater stability towards undesired hydrolytic processes, both enzymatic and spontaneous, and/or optimal pharmacokinetic properties without needing to chemically modify either the specifier or the drug themselves.
- peptidyl derivative pro-drugs of the present invention are selective substrates for drug-activating enzymatic cleavage by tumor-associated fibrinolytic enzymes and are selectively activatible to release cytotoxic levels of pharmacologically active drug at sites exhibiting elevated levels of such fibrinolytic enzyme activity.
- peptidyl derivative pro-drugs of antineoplastic agents which are cyto toxic predominantly to rapidly proliferating cells in accordance with the present invention, should be selectively cytotoxic to those malignant cells which exhibit the specific combination of properties of being rapidly proliferating and exhibiting elevated levels of fibrinolytic enzyme activity.
- the hydrolytic enzyme-activatible pro-drugs in accordance with the present invention may be broadly described as having a molecular structure comprised of a drug moiety and a specifier moiety.
- the specifier moiety by means of its chemical structure, targets the pro-drug to one or more species of hydrolytic enzymes and renders the pro-drug a selective substrate for drug-activating enzymatic cleavage by the target hydrolyt enzyme.
- the drug moiety and the specifier moiety are covalently linked together either directly to form a bipartate molecular structure, or through an intermediate self-immolative connector moiety to form a tripartate molecular structure.
- the covalent linkage between the moieties will be such that the drug moiety is rendered pharmacologically inactive, the site of the drug-activating enzymatic cleavage will be at the bond covalently linking the specifier moiety to its immediately adjacent moiety, and the drug-activating enzymatic cleavage will effect release of the drug moiety in pharmacologically active form.
- the intermediate self-immolative connector moiety when employed in the pro-drug molecule, has a molecular structure such that the drug-activating enzymatic cleavage of the bond covalently linking it to the specifier moiety will initiate spontaneous cleavage of the bond covalently linking it to the drug moiety, to thereby effect release of the drug moiety in pharmacologically active form.
- the peptidyl derivative pro-drugs of antineoplastic agents in accordance with the present invention have an antineoplastic agent as their drug moiety and a peptide as their specifier moiety, and are specifically designed to be selective substrates for drug-activating enzymatic cleavage by one or more tumor-associated proteases selected from the group consisting of fibrinolytic enzymes and blood-coagulating enzymes.
- Blood-coagulating enzymes are those which are involved in the intrinsic or extrinsic system of fibrin clot formation, and include, but are not necessarily limited to, thrombin, thromboplastin, Factor Va, Factor Vila, Factor Villa, Factor IXa, Factor Xa, Factor XIa, and Factor Xlla.
- Fibrinolytic enzymes are those which are involved in the physiological mechanism for dissolving fibrin clots, and include plasmin and plasminogen activator. Recent evidence suggests that all of these proteases are associated with a great many tumors, and that plasmin and plasminogen activator, in particular, are present in these tumors at elevated levels sufficient for pro-drug activation.
- the antineoplastic agent should be one having an unhindered chemically reactive site whose derivatization will inhibit the pharmacological activity of the antineoplastic agent.
- Such reactive site will typically be a free amino group or a free hydroxyl group, since these groups are most readily derivatizable with peptides.
- the reactive site for derivatization of the antineoplastic agent may also be a free sulfhydryl group.
- antineoplastic agents meet the above requirements, including, for example, cytosine arabinoside, adriamycin, daunomycin, 6-thioguanine fluorodeoxyuridine, bis- (2-chloroethyl) amine, phenylene- diamine mustard, 3' -aminothymidine, L-alanosine, 2-amino- thiodiazole, 1 , 4-dihydroxy-5 ,8-bis (2-aminoethylamino) -9 , 10-anthracenedione ,
- the peptide specifier employed for derivatizing the antineoplastic agent so as to convert it into a tumor- specific pro-drug in accordance with the present invention has an amino acid residue sequence specifically tailored so that it will be selectively enzymatically cleaved from the resulting peptidyl derivative pro-drug by one or more of the tumor-associated fibrinolytic and/or blood- coagulating proteases. Examination of the cleavage sites in the natural substrates for these proteases provides a basis for choosing appropriate amino acid residue sequence for the peptide specifier.
- the fibrinolytic and blood-coagulating proteases appear to hav in common a relatively high degree of specificity toward cleavage sites in their natural substrates which have a basic amino acid residue on the carboxyl side thereof, it is preferred to form the peptide specifier with a basic amino acid residue in its C-terminal position, and to carry out the derivatization of the antineoplastic agent with the C-terminus of the peptide specifier.
- Suitable basic amino acid residues for use as the C- terminal amino acid residue of the peptide specifier include lysine, arginine, histidine, ornithine, and citrulline, with lysine and arginine being particularly preferred.
- the amino acid residue in the position immediately adjacent to the C-terminal amino acid residue also appears to play a significant role in imparting the desired protease-specificity to the peptide specifier.
- Such penultimate amino acid residue is preferably a hydrophobic amino acid residue or glycine.
- Suitable hydrophobic amino acid residues include alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan and proline.
- Alanine, leucine and glycine are particularly preferred amino acid residues for use in such penultimate position of the peptide specifier.
- the N-terminal amino acid residue of the peptide specifier is preferably a D-amino acid residue, a protected L-amino acid residue, or protected glycine.
- Suitable protecting groups are well known in the art of peptide chemistry, and include, for example carbobenzoxy (CBZ) , t-butoxycarbonyl (Boc), p-toluene sulfonyl, and benzoyl, with CBZ being particularly preferred.
- the N-terminal amino acid residue is a D-amino acid residue, such as, for example, D-valine or D-isoleucine, since this provides the peptide specifier with better solubility properties than with the protected L-amino acid residue or protected glycine.
- the amino acid residue chain length of the peptide specifier preferably ranges from that of a tripeptide to that of a pentadecapeptide. It will be understood, however, that peptide specifiers as short as dipeptides and longer than pentadecapeptides may also suitably be employed.
- peptide specifier molecules suitable for use in the present invention can be designed and optimized in their selectivity for enzymatic cleavage by a particular one of the tumor-associated fibrinolytic and blood-coagulatin proteases .
- the presently preferred peptide specifiers for use in the present invention are those which are optimized toward the fibrinolytic proteases, plasmin and plasminogen activator. Its high degree of cleavage site specificity makes plasminogen activator a particularly attractive target protease from the standpoint of designing pro-drugs with optimal selectivity.
- plasmin since one plasminogen activator molecule is capable of converting numerous molecules of plasminogen to plasmin, plasmin will generally have a substantially greater tumor-associated concentration than plasminogen activator and, notwithstanding its lower degree of cleavage site specificity, may be more likely to provide a target large enough to generate pharmacologically significant concentrations of the antineoplastic agent from the pro-drug.
- both plasminogen activator, due to its high degree of cleavage site specificity, and plasmin, due to its high tumor-associated concentration appear to be the target proteases of choic in determining optimal amino acid residue sequences for the peptide specifier under the aforementioned general guidelines.
- the C-terminal amino acid residue is preferably lysine, the amino acid residue in the position immediately adjacent to the C-terminal amino acid residue is preferably leucine, and the N-terminal amino acid residue is preferably D-valine or D-isoleucine, Specific examples of this preferred embodiment of peptide specifiers include the tripeptides D-Val-Leu-Lys and
- the amino acid residue sequence preferably substantially mimics the amino acid residue sequence on the carboxyl side of the Arg-Val bond in plasminogen which serves as the site of cleavage of plasminogen by plasminogen activator, with the C-terminal amino acid residue preferably being arginine, and the amino acid residue in the position immediately adjacent to the C-terminal amino acid residue being glycine.
- optimization of the peptide specifier toward one or more of the blood-coagulating enzymes as the target tumor-associated protease may similarly be accomplished by choosing an amino acid residue sequence in accordance with the aforementioned general guidelines, but which substantially mimics the amino acid residue sequence on the carboxyl side of the cleavage site in the appropriate natural or known artificial substrates for the particular enzyme.
- substrates are disclosed by Claeson, et al, "Substrate Structure and Activation Relationship", appearing in New Methods For the Analysis of Coagulation Using Chromogenic Substrates, Ed. I. Witt, Walter de Gruyter, Berlin, New York, Pages 37-54 (1977), incorporated herein by reference.
- Representative peptide specifiers within the scope of the present invention and optimized toward thrombin as the target protease include the tripeptides p-toluene sulfonyl-Gly-Pro-Arg and benzoyl-Phe-Val-Arg.
- a representative peptide specifier in accordance with the present invention and optimized toward Factor Xa as the target protease is the tetrapeptide benzoyl-Ile- Glu-Gly-Arg.
- the peptide specifier is first separately prepared with its C-terminus in the free acid form, and with all of its other reactive groups suitably blocked. Synthesis of the peptide specifier may be carried out by standard peptide synthesis techniques well known in the art, including either solution-phase or solid-phase methods . Particularly where the peptide being synthesized is of relatively short chain length, the solution-phase methods offer certain advantages in that the peptide is directly prepared in the blocked form needed for the subsequent derivatization of the drug, and the intermediates in the synthesis can be purified, insuring product peptide purity. If solid-phase methods are employed, various known techniques may be used for the removal of the blocked peptide from the resin, for example, by using either photocleavable attachment linkages, or by acyl transfer with 2-dimethylaminoethanol. followed by hydrolysis.
- the antineoplastic agent being converted into a pro-drug contains more than one reactive site on its molecule, those reactive sites other than the one being derivatized may be suitably protected prior to the derivatization reaction.
- Any of the conventional protecting groups well known in the art may suitably be used for this purpose.
- the 4-amino group of the base may suitably be protected as the Schiffs base using dimethylformamide dimethyl ketal or diisopropylformamide dimethyl ketal, with the latter providing more favorable organic solubility characteristics important in attaining good product recoveries.
- Deprotection following the derivatization reaction may be effected with trifluoroacetic acid.
- the peptide specifier In preparing the bipartate peptidyl derivative pro-drugs in accordance with the present invention, the peptide specifier, with its C-terminus in the free acid form, and with all of its other reactive groups suitably blocked, is directly reacted with a carboxyl- reactive site of the antineoplastic agent whose derivatization inhibits pharmacological activity, to thereby form a direct covalent linkage between the C- terminus of the peptide specifier and said carboxyl- reactive site of the antineoplastic agent.
- Such covalent linkage will either be an amide linkage, i.e., when the carboxyl-reactive site is a free amino group; or an ester linkage, i.e., when the carboxyl- reactive site is a free hydroxyl group.
- amide linkages are generally preferred in view of the fact that ester-linked pro-drugs tend to lose at least some selectivity due to hydrolysis by nonspecific esterases. Standard ester-forming and amide-forming techniques well known in the art may be used for carrying out the derivatization reaction.
- the amide- linked derivatives may suitably be prepared via a mixed anhydride reaction with the aid of isobutyl chloroformate and either triethylamine or N-methyl morpholine in a suitable solvent such as dimethylformamide or dioxane/tetrahydrofuran.
- a suitable solvent such as dimethylformamide or dioxane/tetrahydrofuran.
- the protecting groups are removed, for example by treatment with trifluoroacetic acid in methylene chloride, to yield the desired peptidyl derivative pro- drug.
- the tripartate pro-drugs in accordance with the present invention employ an intermediate self-immolative connector moiety which spaces and covalently links together the drug moiety and the specifier moiety. Since the self-immolative connector aspect of the present invention is believed to be a novel concept in the design of hydrolytic enzyme-activatible pro-drugs in general, it will be described, first of all, in terms of its broader applications, and thereafter, as it more specifically relates to the peptidyl derivative pro-drugs of antineoplastic agents in accordance with the present invention.
- a self-immolative connector may be defined as a bifunctional chemical moiety which is capable of (1) covalently linking together two spaced chemical moieties into a normally stable tripartate molecule; (2) releasing one of said spaced chemical moieties from the tripartate molecule by means of an enzymatic cleavage; and (3) following said enzymatic cleavage, spontaneously (i.e., non- enzymatically) cleaving from the remainder of the molecule to release the other of said spaced chemical moieties.
- the self-immolative connector is covalently linked at one of its ends to the specifier moiety and covalently linked at its other end to the reactive site of the drug moiety whose derivatization inhibits pharmacological activity, so as to space and covalently link together the specifier moiety and the drug moiety into a tripartate molecule which is stable and pharmacologically inactive in the absence of the target hydrolytic enzyme, but which is enzymatically cleavable by such target hydrolytic enzyme at the bond covalently linking the connector moiety to the specifier moiety to thereby effect release of the specifier moiety from the tripartate molecule.
- a self-immolative connector offers several potential advantages in hydrolytic enzyme-activatible pro-drug design.
- a bipartate pro-drug formed by a direct linkage of the specifier moiety to the drug moiety may not be a suitable substrate for the target hydrolytic enzyme due to steric and/or electronic hindrance at the intended enzymatic cleavage site caused by the close proximity of such site to the drug molecule.
- the drug-activating enzymatic cleavage site may be spaced sufficiently far away from the drug molecule so as to prevent steric and/or electronic interference with the enzymatic cleavage reaction, and without the connector itself preventing release of the free drug in pharmacologically active form following the enzymatic cleavage reaction.
- This should allow construction of many more classes and types of hydrolytic enzyme-activatible pro-drugs.
- the self-immolative connector may provide greater versatility in the type of linkage used for derivatizing the drug, and may enable linkages which are more stable towards undesired hydrolytic processes (both enzymatic and spontaneous) than are the direct specifier-drug linkages.
- the self-immolative connector by providing the self-immolative connector with numerous sites for chemical substitution, it should be possible to design tripartate pro-drugs with optimal pharmacokinetic properties without needing to chejnically modify either the specifier or the drug themselves.
- the specifier and drug should be individually optimized for their own particular tasks, e.g., the specifier might be optimized as a substrate for the desired hydrolytic enzyme and made relatively resistant to hydrolysis by undesired hydrolytic enzymes, and the drug might be optimized for specific inhibition of some target enzyme.
- a connector moiety which has been found to have all of the above-described characteristics rendering it particularly suitable for use as a self-immolative connector, and the manner in which it is employed in the design of hydrolytic enzyme-activatible tripartate pro-drugs in accordance with the present invention, may be represented by the following general formula:
- R 1 is hydrogen or one or more substituent groups which are either electron-donating groups or electron-withdrawing groups
- R 2 and R 3 may be the same or different and are each selected from the group consisting of hydrogen, alkyl, phenyl, and phenyl substituted with either electron-donating groups or electron-withdrawing groups
- R 4 is NH or 0; when R 4 is NH, the specifier moiety is selected from the group consisting of a peptide, an amino acid, a carboxylic acid, and phosphoric acid; when R 4 is O, the specifier moiety is selected from the group consisting of a carboxylic acid, phosphoric acid, and sulfuric acid; and the drug moiety is a normally pharmacologically active agent having a reactive site whose derivatization inhibits pharmacological activity, said reactive site being selected from the group consisting of a free amino group, a free hydroxyl group and a free sulfhydryl group, the covalent linkage between said drug moiety and its adjacent
- any of the common electron-donating and electron- withdrawing groups well known in the art may suitably be employed.
- suitable electron-donating groups include -NH 2, -OH, -OCH 3 , -NHCOCH 3 , -C 6 H 5 , and -CH 3
- suitable electron-withdrawing groups include -NH + (CH 3 ) 3 , -N0 2 , -CN, -S0 3 H, -COOH, -CHO, -COR, -Cl, -Br, -I, and -F .
- the alkyl group will generally be a lower alkyl group but may, if desired, be of longer chain length, for example, up to about 15 carbon atoms .
- Preferred embodiments of the connecto moiety are those in which R 1 is hydrogen, R 2 is hydrogen or methyl, and R 3 is hydrogen or methyl.
- the specifier moiety and the R 4 group together constitute a substrate recognitio site for a particular class of target hydrolytic enzymes which is dependent upon the specific combination of specifier moiety and R 4 group selected.
- the various classes of target hydrolytic enzymes for each specific combination of specifier moiety and R. group within the Formula I definitions set forth above, are listed in Table I, below.
- the carbonate end of the connector moiety enables derivatization of either a free amino group (by forming a carbamate linkage), a free hydroxyl group (by forming a mixed carbonate linkage), or a free sulfhydryl group (by forming a mono-thio mixed carbonate linkage) on a drug molecule.
- pharmacologically active agents having one or more of such reactive groups on their molecule will have their pharmacological activity inhibited by derivatization of such reactive groups, and hence would be suitable for use as the drug moiety of Formula I.
- Representative pharmacologically active agents falling in this category in addition to the various antineoplastic agents previously listed, are set forth, together with their respective types of pharmacological activity and derivatizable sites for inhibition thereof in Table 2 below.
- the specifier moiety and R. together act as a group with poor electron-donating capacity.
- enzymatic cleavage of the bond between the specifier moiety and R 4 by the target hydrolytic enzyme converts R 4 into a strongly electron-donating group, i.e., either NH 2 if R 4 is NH,or OH if R. is 0.
- This electron donating effect greatly labilizes the benzylic bond to oxygen, which spontaneously ionizes. Spontaneous decarboxylation of the carbonate anion will then release the drug moiety in pharmacologically active form.
- the overall release of the drug moiety from the tripartate pro-drug is determined by two processes, namely, (1) the rate of enzymatic hydrolysis of the bond linking the specifier moiety to R 4 , and (2) the rate of ionization of the bond to the benzylic center. If R 1 in Formula I is an electron- donating group, this would tend to decrease process (1) and increase process (2) . On the other hand, if R 1 is an electron-withdrawing group, this would tend to increase process (1) and decrease process (2). The net effect of R 1 on the rate of release of the drug moiety from the tripartate pro-drug may thus be relatively independent of whether R 1 releases or withdraws electrons.
- R 1 can be chosen to be either relatively polar, for example, -NH- or -NH + (CH 3 ) 3 ., or relatively non-polar, for example, -C 6 H 5 or -CH 3 , in order to alter the pharmocokinetic properties of the molecule as desired.
- the resulting tripartate molecules should not vary greatly in the rate of drug release once they equilibrate with the compartment where the target hydrolytic enzyme acts .
- R 1 may thus be chosen to optimize, for example, log P (1-octanol-water partition coefficient) .
- the hydrolytic enzyme-activatible tripartate pro-drugs in accordance with the present invention may be readily synthesized by, first of all, reacting the specifier with a p-substituted benzyl alcohol reactant having the general formula
- the specifier-benzyl alcohol intermediate derivative is then reacted with either phosgene or a chloroformate reagent, such as pentafluorophenyl chloro- formate, pentachloropheny.l chloroformate, or p-nitrophenyl chloroformate, to form a second intermediate derivative.
- This second intermediate derivative will be either a specifier-benzyl chloroformate intermediate derivative, if the reactant is phosgene, or a specifier-benzyl mixed carbonate intermediate derivative, if the reactant is a chloroformate reagent.
- such second intermediate derivative is then reacted with the reactive site of the drug whose derivatization inhibits pharmacological activity (i.e., either a free amino group, a free hydroxyl group, or a free sulfhydryl group), to obtain the pro-drug of Formula I.
- pharmacological activity i.e., either a free amino group, a free hydroxyl group, or a free sulfhydryl group
- the peptide specifier as described in detail hereinabove,with its C-terminus in the free acid form and with all of its other reactive groups suitably blocked with protecting groups, is reacted at its C-terminus with the free amino group of a p-amino benzyl alcohol reactant having the general formula
- This reaction is preferably carried out using a suitable condensing reagent, such as for example, N-ethoxycarbonyl-2-ethoxy-l, 2-dihydroquinoline (EEDQ) in dimethylformamide, to avoid the necessity for protecting the benzylic alcohol function.
- a suitable condensing reagent such as for example, N-ethoxycarbonyl-2-ethoxy-l, 2-dihydroquinoline (EEDQ) in dimethylformamide
- the peptidyl benzyl alcohol is then reacted with either phosgene or a chloroformate reagent, such as pentafluorophenyl chloroformate, pentachlorophenyl chloroformate, or p-nitrophenyl chloroformate, to convert the peptidyl benzyl alcohol into either a peptidyl benzyl chloroformate (if phosgene is used as the reactant) or a peptidyl benzyl mixed carbonate (if a chloroformate reagent is used as the reactant) .
- phosgene or a chloroformate reagent such as pentafluorophenyl chloroformate, pentachlorophenyl chloroformate, or p-nitrophenyl chloroformate
- the peptidyl benzyl chloroformate or peptidyl benzyl mixed carbonate is then reacted with a reactive site (a free amino group, a free hydroxyl group, or a free sulfhydryl group) of the antineoplastic agent whose derivatization inhibits pharmacological activity, to obtain a derivatization reaction product from which the protecting groups are then removed, such derivatization reaction product having the general formula
- the tripartate molecular structure of Formula VI consisting of the peptide specifier moiety, intermediate self-immolative connective moiety, and trie antineoplastic agent moiety, is particularly advantageous when the antineoplastic agent moiety is adriamycin; daunomyci.n., or bis- (2-chloroethyl) amine, since the molecules of these drugs are such as to tend to cause steric or electronic hindrance problems if the intended drug-activating enzymatic cleavage site is in close proximity to the drug molecule.
- the hydrolytic enzyme-activatible pro-drugs of the present invention will generally be administered in the same manner as the parent drug, i.e., orally or parenterally, with parenteral administration, e.g., intravenous, intramuscular or intraarterial, being generally preferred in order to minimize the possibility of premature activation of the pro-drug by non-specific hydrolytic enzymes.
- parenteral administration e.g., intravenous, intramuscular or intraarterial
- the dose levels of the pro-drug should be such as to provide the requisite dose of the free drug. This will generally require that the pro-drug be administered in somewhat larger doses than the parent drug sufficient to allow for the possibility of incomplete activation of the pro-drug into the free drug.
- Boc-D-Val was condensed with Leu-OMe ester using dicyclohexylcarbodiimide (DCC) in dimethylformamide/ methylene chloride solution.
- DCC dicyclohexylcarbodiimide
- the resulting di peptide was converted to the free acid by hydrolyzing the ester with NaOH to yield Boc-D-Val-Leu-OH.
- N ⁇ -CBZ-N ⁇ -Boc-Lys was converted to the methyl ester via treatment with CH 2 N 2 and the amino group freed by hydrogenolysis over Pd/C to yield
- This latter compound was condensed with the Boc-D-Val-Leu-OH (prepared as above) via a mixed anhydride reaction with isobutylchloroformate in dimethylformamide to yield Boc-D-Val-Leu-N ⁇ -Boc-Lys-OMe.
- the crude tripeptide was purified by column chromatography on silica gel, and the methyl ester freed by alkaline hydrolysis to yield Boc-D-Val-Leu-N ⁇ -Boc-
- the peptidyl derivative pro-drug prepared in accordance with Example 1 was tested for its tumor- specific cytotoxic activity by means of an j-n vitro test procedure utilizing a cell culture system with well-matched normal and malignant cells which differed substantially in fibrinolytic enzyme (i-e_., plasmin and plasminogen activator) levels but displayed similar good sensitivity to the free drug.
- the cell culture system employed was chick embryo fibroblasts, both normal and transformed with Rous Sarcoma virus. The transformed cells exhibit a substantially higher level of fibrinolytic enzyme activity than the normal cells.
- the test procedure was carried out as follows. Chick embryo fibroblasts, either normal (N) or transformed with Rous Sarcoma virus (SR) were plated in 35 mm plastic dishes at an initial titer of 1.5 x
- the medium used was Dulbecco's Modified Minimal
- DME Eagle's Medium
- Test drugs which included both the peptidyl derivative pro-drug and, for purposes of comparison, the underivatized parent drug
- 3 H-thymidine was added to each dish for 30 minutes.
- the drug concentration at which incorporation of thymidine is reduced to 50% of the untreated control is determined for each of the two test drugs (i.e., the peptidyl derivative pro-drug and the corresponding underivatized parent drug) against both the normal cells and the transformed cells.
- the therapeutic index of each drug i.e., the ratio of its pharmacological activity to its toxicity
- the therapeutic index for the peptidyl derivative pro-drug in accordance with the present invention was determined to be 5.3, in comparison to a therapeutic index of 1.2 for the corresponding underivatized parent drug.
- the peptidyl derivative pro-drug in accordance with the present invention exhibits an approximately 5-fold improvement in therapeutic index over the corresponding underivatized parent drug.
- peptidyl derivative pro-drugs of the present invention are selective substrates for drug-activating enzymatic cleavage by tumor- associated fibrinolytic enzymes, and are selectively activatible to release cytotoxic levels of pharmacologically active drug at sites exhibiting elevated levels of such fibrinolytic enzyme activity.
- Example 3 Employing a synthesis procedure similar to that described in Example 1, above, the antineoplastic agent, phenylenediamine mustard, was derivatized at its free amino group with D-Val-Leu-Lys peptide specifier to convert it into the peptidyl derivative pro-drug D-Val-Leu-Lys-phenylenediamine mustard.
- the D-Val-Leu-Lys-phenylenediamine mustard pro-drug showed a 7-fold improvement in its therapeutic index in comparison with the underivatized phenylenediamine mustard parent drug.
- Example 4 Employing a synthesis procedure similar to that described in Example 1, above, the antineoplastic agent, adriamycin, was derivatized at its free amino group on daunosamine with the D-Val-Leu-Lys peptide specifier to convert it into D-Val-Leu-Lys-adriamycin pro-drug.
- the D-Val-Leu-Lys-adriamycin pro-drug showed a 6-fold improvement in its therapeutic index, in comparison with the underivatized adriamycin parent drug.
- Example 5 The feasibility of the self-immolative connector aspect of the present invention in the design of hydrolytic enzyme-activatible tripartate pro-drugs was demonstrated by means of the following model study which utilized p-nitroaniline as the "drug" because of the ease of colorimetric detection.
- Th final structure was characterized by NMR and IR spectroscopy.
- elevated levels of fibrinolytic and/ or blood-coagulating enzymes are normally exhibited in the skin, which is the site of intended action of antipsoriasis agents, such as fluocinonide; in the joint, which is the site of intended action of anti-arthritic agents, such as betamethasone; and in the uterus, which is the site of intended action of antifertility or implantation agents such as estrogenic and progestational steroids.
- antipsoriasis agents such as fluocinonide
- anti-arthritic agents such as betamethasone
- antifertility or implantation agents such as estrogenic and progestational steroids.
- any of these drugs could be suitably derivatized with the peptide specifiers as described above to convert them into peptidyl pro-drugs, of either the bipartate or tripartate structure, which are selective substrates for fibrinolytic and/or blood-coagulating proteases so as to be selectively activatible at their site of intended action.
Abstract
Antineoplastic agents are rendered tumor-specific by derivatization with a peptide specifier so as to convert the antineoplastic agent into a pharmacologically inactive pro-drug which is selectively activatible at the tumor site. The peptide specifier has an amino acid residue sequence such that it will be selectively enzymatically cleaved from the antineoplastic agent by tumor-associated fibrinolytic and/or blood-coagulating proteases, such as plasmin and plasminogen activator, so as to effect release of the antineoplastic agent in pharmacologically active form in the vicinity of the tumor. These and other similar hydrolytic enzyme-activatible pro-drugs may be formed with their specifier moiety and their drug moiety covalently linked together through an intermediate self-immolative connector moiety having a molecular structure such that enzymatic cleavage of the bond covalently linking it to the specifier moiety will initiate spontaneous cleavage of the bond covalently linking it to the drug moiety to thereby effect release of the drug in pharmacologically active form.
Description
Description
HYDROLYTIC ENZYME-ACTIVATIBLE PRO-DRUGS
BACKGROUND OF THE INVENTION This invention relates to hydrolytic enzyme- activatible pro-drugs and, in particular, to tumor- specific pro-drugs of antineoplastic agents which are selective substrates for drug-activating enzymatic cleavage by tumor-associated proteases.
One approach to improving the efficiency of drug action and the selectivity of drug delivery is to prepare a reversible derivative of a drug which is itself pharmacologically inactive, but which becomes activated in vivo to liberate the parent drug, typically, but not necessarily, by enzymatic attack. A drug derivative of this type, commonly known as a "pro- drug" or a "latentiated drug", can be tailored to overcome certain undesirable properties of the parent drug, such as, for example, bitterness or tartness, offensive odor, gastric or intestinal upset and irritation, pain on injection, lack of absorption, slow or rapid metabolism, or lack of stability in the bulk state, the dosage form, or in vivo; or it can be designed to be activated selectively at the site of intended action, so that undesired effects can be lessened, The present invention is primarily concerned with pro-drugs of this latter type, which are selectively activatible at the site of intended action, and, in particular, to pro-drugs of antineoplastic agents which are selectively activatible at the tumor site.
One aspect of the present invention, however, is more broadly applicable to pro-drugs in general, as will become more readily apparent hereinbelow.
Many of the antineoplastic agents currently being used in cancer chemotherapy rely for their effectiveness on being selectively cytotoxic to rapidly proliferating cells. In addition to malignant cells, however, certain normal cells are also rapidly proliferating, such as, for example, bone marrow and spleen cells. For this reason bone marrow and spleen toxicity are often limiting factors in the effectiveness of such antineoplastic agents in cancer chemotherapy. One approach in trying to overcome this problem is to design a pro-drug of the antineoplastic agent which will be selectively activatible at the tumor-site, for example, by being a selective substrate for drug-activating enzymatic cleavage by a tumor-associated enzyme. In order for a pro-drug of this type to be useful in cancer chemotherapy, there are several criteria which it must meet. First of all, there must be enough of the activating enzyme in the tumor to generate cytotoxic levels of free drug in the vicinity of the tumor. Secondly, there must be means available to minimize activation of the pro-drug at sites distant from the tumor, and to mitigate the effects of such activation if it occurs. This criterion is clearly related to the first one, since it is the relative amount of tumor-associated and extra-tumor enzymatic activity which is critical for selectivity. Thirdly, the pro-drug must be a suitable substrate for the tumor-associated enzyme under physiological conditions and a poor substrate for other enzymes. Fourthly, the pro-drug must be considerably less toxic than the activated drug, i^.e., at least on the order of ten times less active and preferably on the order of a hundred or a thousand times less active. Finally, the
activated species must have a reasonably short biological half-life so that the toxic effects of the locally activated drug are limited to the tumor and selectivity is not lost by diffusion of the drug away from the site of activation.
A number of attempts have previously been made to develop tumor-specific pro-drugs of antineoplastic agents activatible by tumor-associated enzymes. However, such previous attempts have met with very limited success primarily due to a failure of such pro-drugs to meet one or more of the five criteria set forth above.
Another consideration in the design of hy drolytic enzyme-activatible pro-drugs, in general, is the problem sometimes posed by the nature of the drug molecule being derivatized. If the drug molecule is large or has pronounced polar or apolar character, steric or electronic factors at the intended cleavage site could interfere with the enzymatic cleavage reaction and thereby prevent the pro-drug from being a suitable substrate for the target enzyme.
It has previously been reported that many animal and human tumors exhibit elevated levels of fibrinolytic and blood-coagulating enzyme activity and, in particular, elevated levels of the fibrinolytic enzymes, plasmin and plasminogen activator. Both plasmin and plasminogen activator are proteases with trypsin-like specificity in the sense that they both cleave next to basic amino acids. Substantial information exists concerning the specificity of plasmin and plasminogen activator, based on the use of artificial substrates as well as analysis of the peptide bonds cleaved in the natural substrate. Plasminogen activator shows considerable substrate specificity towards its natural substrate, plasminogen, in which
a single Arg-Val bond is cleaved in converting plasminogen to plasmin. Plasmin is often regarded as a rather unspecific, trypsin-like protease. However, it cleaves a limited number of bonds in dissolving a fibrin clot. Examination of the plasmin cleavage sites in its natural substrate, fibrin, reveal that eleven of the fifteen earliest cleavages are at lysine residues, and in fifteen of the twenty earliest cleavages (including all of the earliest nine cleavages) a hydropho amino acid precedes the lysine or arginine. Hence, the implication is that plasmin is selective for lysine residues preceded by a hydrophobic amino acid residue.
The elevated levels of fibrinolytic and blood- coagulating enzymes found in many tumor cells and the substrate specificity of these proteases have not previously been exploited in the design of tumor- specific pro-drugs of antineoplastic agents. While it is true that various normal cells and tissues, including the lung, kidney, squamous epithelium and activated macrophages, also exhibit elevated levels of these proteases, such normal cells by and large are not rapidly proliferating, and thus should not be highly sensitive to the cytotoxic effects of a DNA synthesis inhibitor released in their vicinity. On the other hand, at least two major sites of high normal cell proliferation, i.e., the bone marrow and spleen, have been reported to be low in fibrinolytic and blood-coagulating enzyme activity. Hence, the specifi combination of rapidly proliferating cells exhibiting high levels of fibrinolytic and blood-coagulating enzyme activity appears to be a characteristic possessed by a great many tumor cells but generally not possessed by normal cells.
SUMMARY OF THE INVENTION It is, accordingly, a primary object of the present invention to provide a pro-drug of an antineoplastic agent which is selectively activatible at the site of the tumor.
Another object of the invention is to provide a tumor-specific pro-drug of an antineoplastic agent in accordance with the preceding object, which is a highly selective substrate for drug-activating enzymatic cleavage by one or more tumor-associated hydrolytic enzymes.
A further object of the invention is to provide a tumor-specific pro-drug of an antineoplastic agent in accordance with the preceding objects, wherein the activating enzyme is one which is present in the tumor in sufficient amounts to generate cytotoxic levels of free drug in the vicinity of the tumor.
Still another object of the invention is to provide a tumor-specific pro-drug of an antineoplastic agent in accordance with the preceding objects, wherein the activating enzyme is one whose presence at sites distant from the tumor is insufficient to generate cytotoxic levels of free drug in the vicinity of such distant sites.
A still further object of the present invention is to provide a tumor-specific pro-drug of an antineoplastic agent in accordance with the preceding objects, which is considerably less toxic than the activated drug.
Yet another object of the present invention is to provide a tumor-specific pro-drug of an antineoplastic agent in accordance with the preceding objects, wherein the activated drug has a reasonably short biological half-life so that the cytotoxic ef-
fects of the locally activated drug are limited to the tumor and selectivity is not lost by diffusion of the drug away from the site of activation.
A yet further object of the present invention is to provide hydrolytic enzyme-activatible pro- drugs, including those of the type set forth in the preceding objects, which include connector means for spacing the drug-activating enzymatic cleavage site sufficiently far away from the drug molecule so as to prevent steric and/or electronic interference with the enzymatic cleavage reaction, which connector means does not in itself prevent release of the free drug in pharmacologically active form following the enzymatic cleavage reaction. The above and other objects are achieved in accordance with the present invention by derivatizing an antineoplastic agent with a peptide specifier at a reactive site appropriate for inhibiting the pharmacological activity of the antineoplastic agent, to thereby convert the antineoplastic agent into a pharmacologically inactive peptidyl derivative pro- drug. The peptide specifier has an amino acid residue sequence specifically tailored so as to render the peptidyl derivative a selective substrate for drug-activating enzymatic cleavage by one or more tumor-associated fibrinolytic and/or blood-coagulating proteases, such as plasmin and plasminogen activator. The enzymatic cleavage reaction will remove the peptide specifier moiety from the pro-drug and effect release of the antineoplastic agent in pharmacologically active form selectively at the tumor site.
In those instances where the drug molecule is large and/or has pronounced polar or apolar character, steric and/or electronic interference of the enzymatic cleavage reaction is avoided in accordance with the present
invention by forming the peptidyl derivative pro-drug with its peptide specifier moiety and its antineoplastic agent moiety covalently linked together through an intermediate self-immolative connector moiety having a molecular structure such that enzymatic cleavage of the bond covalently linking it to the peptide specifier moiety will initiate spontaneous cleavage of the bond covalently linking it to the antineoplastic agent moiety to thereby effect release of the antineoplastic agent in pharmacologically active form. The intermediate self- immolative connector aspect of the present invention is not limited in its application to protease-activatible pro-drugs of antineoplastic agents, but is equally applicable to a variety of other types of hydrolytic enzyme-activatible pro-drugs wherein steric and/or electronic hindrance by the drug molecule might otherwise interfere with the drug-activating enzymatic cleavage reaction. Moreover, the self-immolative connector aspect of the present invention may also be used to impart to the pro-drugs greater stability towards undesired hydrolytic processes, both enzymatic and spontaneous, and/or optimal pharmacokinetic properties without needing to chemically modify either the specifier or the drug themselves. In vitro tests thus far carried out on several protease-activatible peptidyl derivative pro-drugs of antineoplastic agents in accordance with the present invention, show a five to seven-fold improvement over the underivatized parent drug in selective cytotoxic activity against malignant cells exhibiting elevated levels of fibrinolytic enzyme activity versus well-matched (displaying similar good sensitivity to the free drug) normal cells not exhibiting such levels of fibrinolytic enzyme activity. These results are indicative of the fact that the peptidyl derivative pro-drugs of the present invention are selective substrates for drug-activating
enzymatic cleavage by tumor-associated fibrinolytic enzymes and are selectively activatible to release cytotoxic levels of pharmacologically active drug at sites exhibiting elevated levels of such fibrinolytic enzyme activity. Since normal tissues exhibiting such elevated levels of fibrinolytic enzyme activity are, for the most part, limited to those having a low percentage of replicating cells, peptidyl derivative pro-drugs of antineoplastic agents which are cyto toxic predominantly to rapidly proliferating cells in accordance with the present invention, should be selectively cytotoxic to those malignant cells which exhibit the specific combination of properties of being rapidly proliferating and exhibiting elevated levels of fibrinolytic enzyme activity.
DESCRIPTION OF PREFERRED EMBODIMENTS It will be understood that in the following detailed description and appended claims, the abbreviations and nomenclature employed are those which are standard in amino acid and peptide chemistry, and that all amino acids referred to are in the L-form unless otherwise specified.
The hydrolytic enzyme-activatible pro-drugs in accordance with the present invention may be broadly described as having a molecular structure comprised of a drug moiety and a specifier moiety. The specifier moiety, by means of its chemical structure, targets the pro-drug to one or more species of hydrolytic enzymes and renders the pro-drug a selective substrate for drug-activating enzymatic cleavage by the target hydrolyt enzyme. The drug moiety and the specifier moiety are covalently linked together either directly to form a bipartate molecular structure, or through an intermediate self-immolative connector moiety to form a tripartate molecular structure. In either case, the covalent
linkage between the moieties will be such that the drug moiety is rendered pharmacologically inactive, the site of the drug-activating enzymatic cleavage will be at the bond covalently linking the specifier moiety to its immediately adjacent moiety, and the drug-activating enzymatic cleavage will effect release of the drug moiety in pharmacologically active form. The intermediate self-immolative connector moiety, when employed in the pro-drug molecule, has a molecular structure such that the drug-activating enzymatic cleavage of the bond covalently linking it to the specifier moiety will initiate spontaneous cleavage of the bond covalently linking it to the drug moiety, to thereby effect release of the drug moiety in pharmacologically active form.
The peptidyl derivative pro-drugs of antineoplastic agents in accordance with the present invention have an antineoplastic agent as their drug moiety and a peptide as their specifier moiety, and are specifically designed to be selective substrates for drug-activating enzymatic cleavage by one or more tumor-associated proteases selected from the group consisting of fibrinolytic enzymes and blood-coagulating enzymes. Blood-coagulating enzymes are those which are involved in the intrinsic or extrinsic system of fibrin clot formation, and include, but are not necessarily limited to, thrombin, thromboplastin, Factor Va, Factor Vila, Factor Villa, Factor IXa, Factor Xa, Factor XIa, and Factor Xlla. Fibrinolytic enzymes are those which are involved in the physiological mechanism for dissolving fibrin clots, and include plasmin and plasminogen activator. Recent evidence suggests that all of these proteases are associated with a great many tumors, and that plasmin and plasminogen activator, in particular, are present in these tumors at elevated levels sufficient for pro-drug activation.
In order to be suitable for conversion into a pro- drug in accordance with the present invention, the antineoplastic agent should be one having an unhindered chemically reactive site whose derivatization will inhibit the pharmacological activity of the antineoplastic agent. Such reactive site will typically be a free amino group or a free hydroxyl group, since these groups are most readily derivatizable with peptides. However, where an intermediate self-immolative connector is employed in forming the pro-drug, the reactive site for derivatization of the antineoplastic agent may also be a free sulfhydryl group. A number of known antineoplastic agents meet the above requirements, including, for example, cytosine arabinoside, adriamycin, daunomycin, 6-thioguanine fluorodeoxyuridine, bis- (2-chloroethyl) amine, phenylene- diamine mustard, 3' -aminothymidine, L-alanosine, 2-amino- thiodiazole, 1 , 4-dihydroxy-5 ,8-bis (2-aminoethylamino) -9 , 10-anthracenedione ,
C
The peptide specifier employed for derivatizing the antineoplastic agent so as to convert it into a tumor- specific pro-drug in accordance with the present invention has an amino acid residue sequence specifically tailored so that it will be selectively enzymatically cleaved from the resulting peptidyl derivative pro-drug by one or more of the tumor-associated fibrinolytic and/or blood- coagulating proteases. Examination of the cleavage sites in the natural substrates for these proteases provides a basis for choosing appropriate amino acid residue sequence for the peptide specifier. Since at least most of the fibrinolytic and blood-coagulating proteases appear to hav in common a relatively high degree of specificity toward cleavage sites in their natural substrates which have a
basic amino acid residue on the carboxyl side thereof, it is preferred to form the peptide specifier with a basic amino acid residue in its C-terminal position, and to carry out the derivatization of the antineoplastic agent with the C-terminus of the peptide specifier. Suitable basic amino acid residues for use as the C- terminal amino acid residue of the peptide specifier include lysine, arginine, histidine, ornithine, and citrulline, with lysine and arginine being particularly preferred.
The amino acid residue in the position immediately adjacent to the C-terminal amino acid residue also appears to play a significant role in imparting the desired protease-specificity to the peptide specifier. Such penultimate amino acid residue is preferably a hydrophobic amino acid residue or glycine. Suitable hydrophobic amino acid residues include alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan and proline. Alanine, leucine and glycine are particularly preferred amino acid residues for use in such penultimate position of the peptide specifier.
For facilitating preparation of the pro-drug and enhancing its stability against undesired hydrolytic processes, the N-terminal amino acid residue of the peptide specifier is preferably a D-amino acid residue, a protected L-amino acid residue, or protected glycine. Suitable protecting groups are well known in the art of peptide chemistry, and include, for example carbobenzoxy (CBZ) , t-butoxycarbonyl (Boc), p-toluene sulfonyl, and benzoyl, with CBZ being particularly preferred. Most preferably, the N-terminal amino acid residue is a D-amino acid residue, such as, for example, D-valine or D-isoleucine, since this provides the peptide specifier with better solubility properties than with the protected L-amino acid residue or protected glycine.
The amino acid residue chain length of the peptide specifier preferably ranges from that of a tripeptide to that of a pentadecapeptide. It will be understood, however, that peptide specifiers as short as dipeptides and longer than pentadecapeptides may also suitably be employed.
With the foregoing basic considerations serving as a general guideline, numerous specific peptide specifier molecules suitable for use in the present invention can be designed and optimized in their selectivity for enzymatic cleavage by a particular one of the tumor-associated fibrinolytic and blood-coagulatin proteases . Based upon the information which is presently available in regard to the cleavage site specificities and the tumor-associated concentrations of these proteases, the presently preferred peptide specifiers for use in the present invention are those which are optimized toward the fibrinolytic proteases, plasmin and plasminogen activator. Its high degree of cleavage site specificity makes plasminogen activator a particularly attractive target protease from the standpoint of designing pro-drugs with optimal selectivity. On the other hand, since one plasminogen activator molecule is capable of converting numerous molecules of plasminogen to plasmin, plasmin will generally have a substantially greater tumor-associated concentration than plasminogen activator and, notwithstanding its lower degree of cleavage site specificity, may be more likely to provide a target large enough to generate pharmacologically significant concentrations of the antineoplastic agent from the pro-drug. In any event, both plasminogen activator, due to its high degree of cleavage site specificity, and plasmin, due to its high tumor-associated concentration, appear to be the target proteases of choic in determining optimal amino acid residue sequences for the
peptide specifier under the aforementioned general guidelines.
In the peptide specifiers optimized toward plasmin as the target protease, the C-terminal amino acid residue is preferably lysine, the amino acid residue in the position immediately adjacent to the C-terminal amino acid residue is preferably leucine, and the N-terminal amino acid residue is preferably D-valine or D-isoleucine, Specific examples of this preferred embodiment of peptide specifiers include the tripeptides D-Val-Leu-Lys and
D-Ile-Leu-Lys, and the tetrapeptides D-Val-Ser-Leu-Lys and D-Ile-Ser-Leu-Lys.
In the peptide specifiers optimized toward plasminogen activator as the target protease, the amino acid residue sequence preferably substantially mimics the amino acid residue sequence on the carboxyl side of the Arg-Val bond in plasminogen which serves as the site of cleavage of plasminogen by plasminogen activator, with the C-terminal amino acid residue preferably being arginine, and the amino acid residue in the position immediately adjacent to the C-terminal amino acid residue being glycine. Specific examples of this preferred em¬
Optimization of the peptide specifier toward one or more of the blood-coagulating enzymes as the target tumor-associated protease may similarly be accomplished by choosing an amino acid residue sequence in accordance with the aforementioned general guidelines, but which substantially mimics the amino acid residue sequence on the carboxyl side of the cleavage site in the appropriate natural or known artificial substrates for the particular enzyme. Examples of such substrates are disclosed by Claeson, et al, "Substrate Structure and Activation Relationship", appearing in New Methods For the Analysis of Coagulation Using Chromogenic Substrates, Ed. I. Witt, Walter de Gruyter, Berlin, New York, Pages 37-54 (1977), incorporated herein by reference. Representative peptide specifiers within the scope of the present invention and optimized toward thrombin as the target protease, include the tripeptides p-toluene sulfonyl-Gly-Pro-Arg and benzoyl-Phe-Val-Arg. A representative peptide specifier in accordance with the present invention and optimized toward Factor Xa as the target protease is the tetrapeptide benzoyl-Ile- Glu-Gly-Arg.
In the preferred procedure for synthesizing the peptidyl derivative pro-drugs in accordance with the present invention, the peptide specifier is first separately prepared with its C-terminus in the free acid form, and with all of its other reactive groups suitably blocked. Synthesis of the peptide specifier may be carried out by standard peptide synthesis techniques well known in the art, including either solution-phase or solid-phase methods . Particularly where the peptide being synthesized is of relatively short chain length, the solution-phase methods offer certain advantages in that the peptide is directly prepared in the blocked form needed for the subsequent derivatization of the drug, and the intermediates in the synthesis can be purified,
insuring product peptide purity. If solid-phase methods are employed, various known techniques may be used for the removal of the blocked peptide from the resin, for example, by using either photocleavable attachment linkages, or by acyl transfer with 2-dimethylaminoethanol. followed by hydrolysis.
If the antineoplastic agent being converted into a pro-drug contains more than one reactive site on its molecule, those reactive sites other than the one being derivatized may be suitably protected prior to the derivatization reaction. Any of the conventional protecting groups well known in the art may suitably be used for this purpose. For example, in derivatizing the 5'-hydroxyl group of cytosine arabinoside, the 4-amino group of the base may suitably be protected as the Schiffs base using dimethylformamide dimethyl ketal or diisopropylformamide dimethyl ketal, with the latter providing more favorable organic solubility characteristics important in attaining good product recoveries. Deprotection following the derivatization reaction may be effected with trifluoroacetic acid. Another instance where protecting groups might be used to achieve more favorable organic solubility characteristics would be in the derivatization of the 2- amino group of 6-thioguanine, wherein benzylation of the 6-thιo group and at the N4 position will increase the solubility of the parent drug. Deprotection of S and N benzyl protecting groups following the derivatization reaction can be accomplished by treatment with sodium in liquid ammonia.
In preparing the bipartate peptidyl derivative pro-drugs in accordance with the present invention, the peptide specifier, with its C-terminus in the free acid form, and with all of its other reactive groups suitably blocked, is directly reacted with a carboxyl- reactive site of the antineoplastic agent whose
derivatization inhibits pharmacological activity, to thereby form a direct covalent linkage between the C- terminus of the peptide specifier and said carboxyl- reactive site of the antineoplastic agent. Such covalent linkage will either be an amide linkage, i.e., when the carboxyl-reactive site is a free amino group; or an ester linkage, i.e., when the carboxyl- reactive site is a free hydroxyl group. Where a choice is available between synthesizing the pro-drug with either an amide linkage or an ester linkage, amide linkages are generally preferred in view of the fact that ester-linked pro-drugs tend to lose at least some selectivity due to hydrolysis by nonspecific esterases. Standard ester-forming and amide-forming techniques well known in the art may be used for carrying out the derivatization reaction. For example, the amide- linked derivatives may suitably be prepared via a mixed anhydride reaction with the aid of isobutyl chloroformate and either triethylamine or N-methyl morpholine in a suitable solvent such as dimethylformamide or dioxane/tetrahydrofuran. Following the derivatization reaction, the protecting groups are removed, for example by treatment with trifluoroacetic acid in methylene chloride, to yield the desired peptidyl derivative pro- drug.
The tripartate pro-drugs in accordance with the present invention employ an intermediate self-immolative connector moiety which spaces and covalently links together the drug moiety and the specifier moiety. Since the self-immolative connector aspect of the present invention is believed to be a novel concept in the design of hydrolytic enzyme-activatible pro-drugs in general, it will be described, first of all, in terms of its broader applications, and thereafter,
as it more specifically relates to the peptidyl derivative pro-drugs of antineoplastic agents in accordance with the present invention.
In its broadest sense, a self-immolative connector may be defined as a bifunctional chemical moiety which is capable of (1) covalently linking together two spaced chemical moieties into a normally stable tripartate molecule; (2) releasing one of said spaced chemical moieties from the tripartate molecule by means of an enzymatic cleavage; and (3) following said enzymatic cleavage, spontaneously (i.e., non- enzymatically) cleaving from the remainder of the molecule to release the other of said spaced chemical moieties. As applied to the design of hydrolytic enzyme-activatible pro-drugs in accordance with the present invention, the self-immolative connector is covalently linked at one of its ends to the specifier moiety and covalently linked at its other end to the reactive site of the drug moiety whose derivatization inhibits pharmacological activity, so as to space and covalently link together the specifier moiety and the drug moiety into a tripartate molecule which is stable and pharmacologically inactive in the absence of the target hydrolytic enzyme, but which is enzymatically cleavable by such target hydrolytic enzyme at the bond covalently linking the connector moiety to the specifier moiety to thereby effect release of the specifier moiety from the tripartate molecule. Such enzymatic cleavage, in turn, will activate the self-immolating character of the connector moiety and initiate spontaneous cleavage of the bond covalently linking the connector moiety to the drug moiety, to thereby effect release of the drug in pharmacologically active form.
A self-immolative connector offers several potential advantages in hydrolytic enzyme-activatible pro-drug design. First of all, in those instances where the drug molecule being derivatized is large and/or has pronounced polar or apolar character, a bipartate pro-drug formed by a direct linkage of the specifier moiety to the drug moiety may not be a suitable substrate for the target hydrolytic enzyme due to steric and/or electronic hindrance at the intended enzymatic cleavage site caused by the close proximity of such site to the drug molecule. By inserting an intermediate self-immolative connector moiety between the specifier moiety and the drug moiety, the drug-activating enzymatic cleavage site may be spaced sufficiently far away from the drug molecule so as to prevent steric and/or electronic interference with the enzymatic cleavage reaction, and without the connector itself preventing release of the free drug in pharmacologically active form following the enzymatic cleavage reaction. This should allow construction of many more classes and types of hydrolytic enzyme-activatible pro-drugs. Secondly, by varying the functionality of the drug-derivatizing end of the self-immolative connector from that of the specifier, the self-immolative connector may provide greater versatility in the type of linkage used for derivatizing the drug, and may enable linkages which are more stable towards undesired hydrolytic processes (both enzymatic and spontaneous) than are the direct specifier-drug linkages. Thirdly, by providing the self-immolative connector with numerous sites for chemical substitution, it should be possible to design tripartate pro-drugs with optimal pharmacokinetic properties without needing to chejnically modify either the specifier or the drug
themselves. This should allow the specifier and drug to be individually optimized for their own particular tasks, e.g., the specifier might be optimized as a substrate for the desired hydrolytic enzyme and made relatively resistant to hydrolysis by undesired hydrolytic enzymes, and the drug might be optimized for specific inhibition of some target enzyme.
A connector moiety which has been found to have all of the above-described characteristics rendering it particularly suitable for use as a self-immolative connector, and the manner in which it is employed in the design of hydrolytic enzyme-activatible tripartate pro-drugs in accordance with the present invention, may be represented by the following general formula:
wherein R1 is hydrogen or one or more substituent groups which are either electron-donating groups or electron-withdrawing groups; R2 and R3 may be the same or different and are each selected from the group consisting of hydrogen, alkyl, phenyl, and phenyl substituted with either electron-donating groups or electron-withdrawing groups; R4 is NH or 0; when R4 is NH, the specifier moiety is selected from the group consisting of a peptide, an amino acid, a carboxylic acid, and phosphoric acid; when R4 is O, the specifier moiety is selected from the group consisting of a carboxylic acid, phosphoric acid, and sulfuric acid; and the drug moiety is a normally pharmacologically active agent having a reactive site whose derivatization inhibits pharmacological activity, said reactive site being selected from the group consisting of a
free amino group, a free hydroxyl group and a free sulfhydryl group, the covalent linkage between said drug moiety and its adjacent carbonyl group being at said reactive site so as to inhibit the pharmacological activity of said drug moiety.
In the above definitions of R1, R2 and R3, any of the common electron-donating and electron- withdrawing groups well known in the art may suitably be employed. By way of example suitable electron- donating groups include -NH2, -OH, -OCH3, -NHCOCH3, -C6H5, and -CH3; and suitable electron-withdrawing groups include -NH+(CH3)3, -N02, -CN, -S03H, -COOH, -CHO, -COR, -Cl, -Br, -I, and -F . In the above definitions of R2 and R3 , the alkyl group will generally be a lower alkyl group but may, if desired, be of longer chain length, for example, up to about 15 carbon atoms . Preferred embodiments of the connecto moiety are those in which R1 is hydrogen, R2 is hydrogen or methyl, and R3 is hydrogen or methyl. In Formula I, above, the specifier moiety and the R4 group together constitute a substrate recognitio site for a particular class of target hydrolytic enzymes which is dependent upon the specific combination of specifier moiety and R4 group selected. The various classes of target hydrolytic enzymes for each specific combination of specifier moiety and R. group within the Formula I definitions set forth above, are listed in Table I, below.
The carbonate end of the connector moiety enables derivatization of either a free amino group (by forming a carbamate linkage), a free hydroxyl group (by forming a mixed carbonate linkage), or a free sulfhydryl group (by forming a mono-thio mixed carbonate linkage) on a drug molecule. A wide variety of different types of pharmacologically active agents having one or more of such reactive groups on their molecule will have their pharmacological activity inhibited by derivatization of such reactive groups, and hence would be suitable for use as the drug moiety of Formula I. Representative pharmacologically active agents falling in this category, in addition to the various antineoplastic agents previously listed, are set forth, together with their respective types of pharmacological activity and derivatizable sites for inhibition thereof in Table 2 below.
The theory underlying the mechanism of the self- immolative connector in accordance with the present invention, is explained by the following reaction scheme:
The specifier moiety and R. together act as a group with poor electron-donating capacity. However, enzymatic cleavage of the bond between the specifier moiety and R4 by the target hydrolytic enzyme converts R4 into a strongly electron-donating group, i.e., either NH2 if R4 is NH,or OH if R. is 0. This electron donating effect greatly labilizes the benzylic bond to oxygen, which spontaneously ionizes. Spontaneous decarboxylation of the carbonate anion will then release the drug moiety in pharmacologically active form.
The overall release of the drug moiety from the tripartate pro-drug is determined by two processes, namely, (1) the rate of enzymatic hydrolysis of the bond linking the specifier moiety to R4, and (2) the rate of ionization of the bond to the benzylic center. If R1 in Formula I is an electron- donating group, this would tend to decrease process (1) and increase process (2) . On the other hand, if R1 is an electron-withdrawing group, this would tend to increase process (1) and decrease process (2). The net effect of R1 on the rate of release of the drug moiety from the tripartate pro-drug may thus be relatively independent of whether R1 releases or withdraws electrons. The system is thus at least partially buffered against the electronic nature of R1, at least over a certain range. This means thatR1 can be chosen to be either relatively polar, for example, -NH- or -NH+(CH3)3., or relatively non-polar, for example, -C6H5 or -CH3, in order to alter the pharmocokinetic properties of the molecule as desired. The resulting tripartate molecules should not vary greatly in the rate of drug release once they equilibrate with the compartment where the target hydrolytic enzyme acts .R1 may thus be chosen to optimize, for example, log P (1-octanol-water partition coefficient) .
In regard to R„ and R-. in Formula I, the predominant effect of these groups will be on the rate of ionization of the bond to the benzylic center. Electron-donating substituents on these groups will tend to increase the ionization rate, while electron- withdrawing substituents on these groups will tend to decrease the ionization rate.
The hydrolytic enzyme-activatible tripartate pro-drugs in accordance with the present invention, may be readily synthesized by, first of all, reacting the specifier with a p-substituted benzyl alcohol reactant having the general formula
*2-,
H-: V >-C-OH (ID
R3
R i |
"^ l wherein R1 , R 2 R3 and R4 have the same meanings as defined above, to obtain a specifier-benzyl alcohol intermediate derivative having the general formula
Specifier-R.-</ \)-C-OH (III)
The specifier-benzyl alcohol intermediate derivative is then reacted with either phosgene or a chloroformate reagent, such as pentafluorophenyl chloro- formate, pentachloropheny.l chloroformate, or p-nitrophenyl chloroformate, to form a second intermediate derivative. This second intermediate derivative will be either a specifier-benzyl chloroformate intermediate derivative, if the reactant is phosgene, or a specifier-benzyl mixed carbonate intermediate derivative, if the reactant is a chloroformate reagent. In either case, such second intermediate derivative is then reacted with the reactive site of the drug whose derivatization inhibits pharmacological activity (i.e., either a free amino group, a free hydroxyl group, or a free sulfhydryl group), to obtain the pro-drug of Formula I.
Applying the above-described general procedure to the synthesis of tripartate peptidyl derivative pro-drugs of antineoplastic agents in accordance with the present invention, the peptide specifier, as described in detail hereinabove,with its C-terminus in the free acid form and with all of its other reactive groups suitably blocked with protecting groups, is reacted at its C-terminus with the free amino group of a p-amino benzyl alcohol reactant having the general formula
wherein R- , R„ , R and R . have the same meanings as defined above, to obtain a peptidyl benzyl alcohol having the general formula
This reaction is preferably carried out using a suitable condensing reagent, such as for example, N-ethoxycarbonyl-2-ethoxy-l, 2-dihydroquinoline (EEDQ) in dimethylformamide, to avoid the necessity for protecting the benzylic alcohol function. The peptidyl benzyl alcohol is then reacted with either phosgene or a chloroformate reagent, such as pentafluorophenyl chloroformate, pentachlorophenyl chloroformate, or p-nitrophenyl chloroformate, to convert the peptidyl benzyl alcohol into either a peptidyl benzyl chloroformate (if phosgene is used as the reactant) or a peptidyl benzyl mixed carbonate (if a chloroformate reagent is used as the reactant) . The peptidyl benzyl chloroformate or peptidyl benzyl mixed carbonate is
then reacted with a reactive site (a free amino group, a free hydroxyl group, or a free sulfhydryl group) of the antineoplastic agent whose derivatization inhibits pharmacological activity, to obtain a derivatization reaction product from which the protecting groups are then removed, such derivatization reaction product having the general formula
In preparing the peptidyl derivative pro-drugs of antineoplastic agents in accordance with the present invention, the tripartate molecular structure of Formula VI, consisting of the peptide specifier moiety, intermediate self-immolative connective moiety, and trie antineoplastic agent moiety, is particularly advantageous when the antineoplastic agent moiety is adriamycin; daunomyci.n., or bis- (2-chloroethyl) amine, since the molecules of these drugs are such as to tend to cause steric or electronic hindrance problems if the intended drug-activating enzymatic cleavage site is in close proximity to the drug molecule.
These problems are minimized by the spacing provided by the self-immolative connector moiety.
The hydrolytic enzyme-activatible pro-drugs of the present invention, whether of the bipartate or tripartate molecular structure, will generally be administered in the same manner as the parent drug, i.e., orally or parenterally, with parenteral administration, e.g., intravenous, intramuscular or intraarterial, being generally preferred in order to minimize the possibility of premature activation of the pro-drug by non-specific hydrolytic enzymes. The dose levels of the pro-drug should be such
as to provide the requisite dose of the free drug. This will generally require that the pro-drug be administered in somewhat larger doses than the parent drug sufficient to allow for the possibility of incomplete activation of the pro-drug into the free drug.
The invention will be further illustrated by way of the following examples.
Example 1 (A) Synthesis of Peptide Specifier
Boc-D-Val was condensed with Leu-OMe ester using dicyclohexylcarbodiimide (DCC) in dimethylformamide/ methylene chloride solution. The resulting di peptide was converted to the free acid by hydrolyzing the ester with NaOH to yield Boc-D-Val-Leu-OH. Nε-CBZ-Nε-Boc-Lys was converted to the methyl ester via treatment with CH2N2 and the amino group freed by hydrogenolysis over Pd/C to yield This latter compound was condensed with the Boc-D-Val-Leu-OH (prepared as above) via a mixed anhydride reaction with isobutylchloroformate in dimethylformamide to yield Boc-D-Val-Leu-Nε-Boc-Lys-OMe. The crude tripeptide was purified by column chromatography on silica gel, and the methyl ester freed by alkaline hydrolysis to yield Boc-D-Val-Leu-Nε-Boc-
Lys-OH.
(B) Synthesis of Bipartate Pro-Drug
The antineoplastic agent AT-125 having the formula
was derivatized at its free amino group by condensing it with the protected peptide specifier Boc-D-Val-Leu-Nε-Boc-Lys-OH (prepared as above) via a mixed anhydride reaction with isobutyl- chloroformate in dioxane/tetrahydrofuran. The resulting product was deprotected with trifluoro acetic acid (TFA) in methylene chloride to yield the desired pro-drug D-Val-Leu-Lys-AT-125. A portion of this peptidyl derivative pro-drug was treated with trypsin in Tris buffer. Two products were obtained which showed Rf on TLC silica plates corresponding to the tri peptide D-Val-Leu-Lys-OH and the free drug AT-125. This demonstrates that the pro-drug is a sub- strate for trypsin and, presumably, other trypsin like proteases such as plasmin and plasminogen activator, which generally show a specificity similar to that of trypsin. A similar result was obtained with plasmin.
Example 2
The peptidyl derivative pro-drug prepared in accordance with Example 1, was tested for its tumor- specific cytotoxic activity by means of an j-n vitro test procedure utilizing a cell culture system with well-matched normal and malignant cells which differed substantially in fibrinolytic enzyme (i-e_., plasmin and plasminogen activator) levels but displayed similar good sensitivity to the free drug. The cell culture system employed was chick embryo fibroblasts, both normal and transformed with Rous Sarcoma virus. The transformed cells exhibit a substantially higher level of fibrinolytic enzyme activity than the normal cells. The test procedure was carried out as follows.
Chick embryo fibroblasts, either normal (N) or transformed with Rous Sarcoma virus (SR) were plated in 35 mm plastic dishes at an initial titer of 1.5 x
10 5 cells per dish (N) or 3 x 105 cells per dish (SR) . Allowing for the difference in plating efficiencies between normal and transformed cells, this leads to similar numbers of cells per plate.
The medium used was Dulbecco's Modified Minimal
Eagle's Medium (DME) supplemented with 10% Tryptose- Phosphate broth, 4% calf serum, and 1% chick serum. Cells grow exponentially in this medium with a doubling time of 18 to 20 hours. After 24 hours the cells were changed to DME medium containing 5% chick serum and lacking Tryptose-Phosphate broth and calf serum. After a further 18 hours, the test drugs (which included both the peptidyl derivative pro-drug and, for purposes of comparison, the underivatized parent drug) were added at various concentrations for a further 5 hours. Finally, in order to measure DNA synthesis 3H-thymidine at a final concentration of 1 microcurie/ml was added to each dish for 30 minutes. The medium was removed and the cells were incubated with cold 5% trichloroacetic acid for a further 15 minutes. After 3 further washes with cold trichloroacetic acid, the DNA was hydrolyzed with 10% trichloroacetic acid at 70 °C for two hours. The solubilized material was counted in an Omnifluor- Triton-X-100 scintillation fluid. Control experiments have demonstrated that this measurement of thymidine incorporation into DNA corresponds to cell numbers as determined in a Coulter counter. By means of plotting the residual 3H-thymidine incorporation as a function of drug concentration compared to untreated control, the ED50 (i.e. , the drug concentration at which incorporation of thymidine
is reduced to 50% of the untreated control) is determined for each of the two test drugs (i.e., the peptidyl derivative pro-drug and the corresponding underivatized parent drug) against both the normal cells and the transformed cells. The therapeutic index of each drug (i.e., the ratio of its pharmacological activity to its toxicity) is then determined as the ratio of its EDo,.u-, against the normal cells to its ED50 against the transformed cells. Following this procedure, the therapeutic index for the peptidyl derivative pro-drug in accordance with the present invention was determined to be 5.3, in comparison to a therapeutic index of 1.2 for the corresponding underivatized parent drug. Thus, the peptidyl derivative pro-drug in accordance with the present invention exhibits an approximately 5-fold improvement in therapeutic index over the corresponding underivatized parent drug.
The above-described test results are indicative of the fact that the peptidyl derivative pro-drugs of the present invention are selective substrates for drug-activating enzymatic cleavage by tumor- associated fibrinolytic enzymes, and are selectively activatible to release cytotoxic levels of pharmacologically active drug at sites exhibiting elevated levels of such fibrinolytic enzyme activity.
Example 3 Employing a synthesis procedure similar to that described in Example 1, above, the antineoplastic agent, phenylenediamine mustard, was derivatized at its free amino group with D-Val-Leu-Lys peptide specifier to convert it into the peptidyl derivative pro-drug D-Val-Leu-Lys-phenylenediamine mustard.
When tested by means of the in vitro assay described in Example 2, above, the D-Val-Leu-Lys-phenylenediamine mustard pro-drug showed a 7-fold improvement in its therapeutic index in comparison with the underivatized phenylenediamine mustard parent drug.
Example 4 Employing a synthesis procedure similar to that described in Example 1, above, the antineoplastic agent, adriamycin, was derivatized at its free amino group on daunosamine with the D-Val-Leu-Lys peptide specifier to convert it into D-Val-Leu-Lys-adriamycin pro-drug. When tested by means of the in vitro assay described in Example 2, above, the D-Val-Leu-Lys-adriamycin pro-drug showed a 6-fold improvement in its therapeutic index, in comparison with the underivatized adriamycin parent drug.
Example 5 The feasibility of the self-immolative connector aspect of the present invention in the design of hydrolytic enzyme-activatible tripartate pro-drugs was demonstrated by means of the following model study which utilized p-nitroaniline as the "drug" because of the ease of colorimetric detection.
Synthesis of the tripartate pro-drug model was carried out as follows. N -t-Boc-N -TFA lysine was coupled to p-aminobenzyl alcohol using N-ethoxycarbonyl- 2-ethoxy-l, 2-dihydroquinoline (EEDQ) in dimethylformamide. The product was purified by crystallization from ethyl acetate: ether. Next this material was reacted with p-nitrophenylisocyanate in dry pyridine to yield
which was purified by preparative TLC on silica. Finally, the TFA group was removed with tetramethyl- guanidine in acetonitrile-water 1:1 to yield the tripartate pro-drug model having the formula
Th final structure was characterized by NMR and IR spectroscopy.
In order to demonstrate the possibility of self- immolation with this tripartate pro-drug model, it was dissolved in 1 ml 50 mM Bis-Tris-Cl buffer pH 6.7 at 1 mM and treated with 2 μg of trypsin. There was an instantaneous release of p-nitroaniline as measured by the increase of optical density at 405 nm. The rate of release of p-nitroaniline was comparable to the rate of release expected for cleavage of the
Lys-anilide bond, and no lag was noted. TLC analysis showed the expected products Nα-Boc-Lys-OH, p-aminobenzy alcohol, and p-nitroaniline. The release of p-nitroaniline was blocked by prior treatment of trypsin with tosyl-lysyl chloromethyl ketone (TLCK) .
Two similar tripartate pro-drug models were similarly synthesized, one with one of the benzylic hydrogens replaced by a methyl group, and the other with p-nitroaniline replaced by aniline. In both cases, TLC analysis again showed that trypsin hydrolysis released the expected products, including p-nitroaniline or aniline. This was confirmed spectrophotometrically in the case of the p-nitroaniline derivative.
The above-described model studies demonstrate the feasibility under physiological conditions of the self-immolation of the intermediate connector moiety in the hydrolytic enzyme-activatible tripartate pro-drugs in accordance with the present invention.
While the fibrinolytic and blood-coagulating enzyme- activatible peptidyl derivative pro-drugs in accordance with the present invention have been described with particular reference to the preferred embodiments thereof wherein the drug moiety is an antineoplastic agent, it will be understood that the drug moiety, in either the bipartate or tripartate structure, could be any normally pharmacologically active compound which is suitably convertible into a pro-drug by derivatization with the peptide specifiers described above and whose site of intended action is known to exhibit elevated levels of fibrinolytic and/or blood-coagulating enzyme activity. By way of example, elevated levels of fibrinolytic and/ or blood-coagulating enzymes are normally exhibited in the skin, which is the site of intended action of antipsoriasis agents, such as fluocinonide; in the joint, which is the site of intended action of anti-arthritic agents, such as betamethasone; and in the uterus, which is the site of intended action of antifertility or implantation agents such as estrogenic and progestational steroids. Any of these drugs could be suitably derivatized with the peptide specifiers as described above to convert them into peptidyl pro-drugs, of either the bipartate or tripartate structure, which are selective substrates for fibrinolytic and/or blood-coagulating proteases so as to be selectively activatible at their site of intended action.
Claims
1. A tumor-specific pro-drug of an antineoplastic agent comprising a peptidyl derivative of said antineoplastic agent, said peptidyl deriva tive being a selective substrate for drug-activating enzymatic cleavage by one or more tumor-associated proteases selected from the group consisting of fibrinolytic enzymes and blood-coagulating enzymes.
2. The pro-drug of Claim 1, wherein said tumor-associated protease is a fibrinolytic enzyme selected from the group consisting of plasmin and plasminogen activator.
3. The pro-drug of Claim 1, wherein said tumor-associated protease is a blood-coagulating enzyme selected from the group consisting of thrombin, thrombo plastin. Factor Va, Factor Vila, Factor Villa, Factor IXa,Factor Xa, Factor XIa, and Factor Xlla.
4. The pro-drug of Claim 1, wherein the molecular structure of said peptidyl derivative is comprised of a peptide specifier moiety and an antineoplastic agent moiety, said two moieties being covalently linked together either directly or through an intermediate self-immolative connector moiety in a manner such that said antineoplastic agent moiety is rendered pharmacologically inactive, the site of said drug-activating enzymatic cleavage will be at the bond covalently linking said peptide specifier moiety to its immediately adjacent moiety, and said drug-activating enzymatic cleavage will effect release of said antineoplastic agent moiety in pharmacologically active form.
5. The pro-drug of Claim 4, wherein the covalent linkage of said peptide specifier moiety to its immediately adjacent moiety is at the C- terminus of said peptide specifier moiety, and the C-terminal amino acid residue of said peptide specifier moiety is a basic amino acid residue.
6. The pro-drug of Claim 5, wherein said C-terminal amino acid residue is arginine or lysine.
7. The pro-drug of Claim 5, wherein said peptide specifier moiety contains a hydrophobic amino acid residue or glycine in the position immediately adjacent to said C-terminal amino acid residue.
8. The pro-drug of Claim 7 , wherein said hydrophobic amino acid residue is selected from the group consisting of alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan and proline.
9. The pro-drug of Claim 5 , wherein the N-terminal amino acid residue of said peptide specifier moiety is a D-amino acid residue, a protected L-amino acid residue, or protected glycine.
10. The pro-drug of Claim 5, wherein said peptide specifier moiety has an amino acid residue chain length ranging from that of a tripeptide to that of a pentadecapeptide.
11. The pro-drug of Claim 10, wherein said peptide specifier moiety contains a hydro- phobic amino acid residue or glycine in the position immediately adjacent to said C-terminal amino acid residue, and the N-terminal amino acid residue of said peptide specifier moiety is a D-amino acid, residue, a protected L-amino acid residue or protected glycine.
12. The pro-drug of Claim 10, wherein the amino acid residue sequence in said peptide specifier moiety is such that its C-terminal amino acid residue is arginine or lysine, its amino acid residue in the position immediately adjacent to said C-terminal amino acid residue is alanine, leucine, or glycine, and its N-terminal amino acid residue is a D-amino acid residue, a protected L-amino acid residue or protected glycine.
13. The pro-drug of Claim 12, wherein said
C-terminal amino acid residue is lysine, said amino acid residue in the position immediately adjacent to said C-terminal amino acid residue is leucine, and said N-terminal amino acid residue is D-valine or D-isoleucine.
14. The pro-drug of Claim 12, wherein the amino acid residue sequence in said peptide specifier moiety substantially mimics the amino acid residue sequence on the carboxyl side of the Arg-Val bond in plasminogen which serves as the site of cleavage of plasminogen by plasminogen activator, with said C-terminal amino acid residue being arginine, and said amino acid residue in the position immediately adjacent to said C-terminal amino acid residue being glycine.
15. The pro-drug of Claim 4, wherein said peptidyl derivative has a bipartate molecular structure consisting of said peptide specifier moiety and said antineoplastic agent moiety, said two moieties being directly covalently linked together by means of a covalent linkage formed between the C-terminus of said peptide specifier moiety and a carboxyl-reactive site of said antineoplastic agent moiety whose derivatization inhibits pharmacological activity.
16. The pro-drug of Claim 15, wherein said covalent linkage is an amide linkage formed between the C-terminus of said peptide specifier moiety and a free amino group of said antineo- plastic agent moiety.
17. The pro-drug of Claim 15, wherein said covalent linkage is an ester linkage formed between the C-terminus of said peptide specifier moiety and a free hydroxyl group of said antineoplastic agent moiety.
18. The pro-drug of Claim 4, wherein said peptidyl derivative has a tripartate molecular structure consisting of said peptide specifier moiety, said intermediate self-immolative connector moiety and said antineoplastic agent moiety, said intermediate self-immolative connector moiety being covalently linked at its one end to the C- terminus of said peptide specifier moiety and covalently linked at its other end to a reactive site of said antineoplastic agent moiety whose derivatization inhibits pharmacological activity, said intermediate self-immolative connector moiety having a molecular structure such that said drug- activating enzymatic cleavage of the bond covalently linking it to said peptide specifier moiety will initiate spontaneous cleavage of the bond covalently linking it to said antineoplastic agent moiety to thereby effect release of said antineoplastic agent moiety in pharmacologically active form.
19. The pro-drug of Claim 18 , wherein said intermediate self-immolative connector moiety has the general formula :
wherein R. is hydrogen or one or more substituent groups which are either electron-donating groups or electron-withdrawing groups, and R2 and. R3 may be the same or different and are each selected from the group consisting of hydrogen, alkyl, phenyl, and phenyl substituted with either electron-donating groups or electron-withdrawing groups, said connector moiety having its terminal amino group covalently linked to the C- terminus of said peptide specifier moiety and its terminal carbonyl group covalently linked to said reactive site of said antineoplastic agent moiety.
20. The pro-drug of Claim 19, whereinR1 is hydrogen, R2 is hydrogen or methyl, and Ri3is hydrogen or methyl.
21. The pro-drug of Claim 19, wherein said reactive site of said antineoplastic agent moiety is a free amino group, a free hydroxyl group, or a free sulfhydryl group.
22. The pro-drug of Claim 21, wherein said antineoplastic agent moiety is selected from the group consisting of adriamycin, daunomycin, and bis- (2- chloroethy1) amine.
23. The pro-drug of Claim 4, wherein the covalent linkage of said antineoplastic agent moiety to its immediately adjacent moiety is at a reactive site of said antineoplastic agent moiety whose derivatization inhibits pharmacological activity.
24. The pro-drug of Claim 23, wherein said reactive site of said antineoplastic agent moiety is a free amino group, a free hydroxyl group, or a free sulfhydryl group.
25. The pro-drug of Claim 24, wherein said antineoplastic agent moiety is selected from the group consisting of cytosine arabinoside, adriamycin, daunomycin, 6-thioguanine, fluorodeoxyuridine, bis- (2- chloroethyl) amine, phenylenediamine mustard, 3'-amino- thymidine, L-alanosine, 2-aminothiodiazole, 1,4-dihydroxy-
5 ,8-bis (2-aminoethylamino) -9,10-anthracenedione,
26. The pro-drug of Claim 25, wherein said peptide specifier moiety has an amino acid residue chain length ranging from that of a tripeptide to that of a pentadecapeptide, the covalent linkage of said peptide specifier moiety to its immediately adjacent moiety is at the C-terminus of said peptide specifier moiety, and the amino acid residue sequence in said peptide specifier moiety is such that its C- terminal amino acid residue is a basic amino acid residue, its amino acid residue in the position immediately adjacent to said C-terminal amino acid residue is a hydrophobic amino acid residue or glycine, and its N-terminal amino acid residue is a D-amino acid residue, a protected L-amino acid residue or protected glycine.
27. A method of rendering an antineoplastic agent tumor-specific which comprises derivatizing said antineoplastic agent either directly or through an intermediate self-immolative connector with a peptide specifier at a reactive site appropriate for inhibiting the pharmacological activity of said antineoplastic agent, said peptide specifier having an amino acid residue sequence such that it will be selectively enzymatically cleaved from said antineoplastic agent by one or more tumor-associated proteases selected from the group consisting of fibrinolytic enzymes and blood- coagulating enzymes so as to effect release of said antineoplastic agent in pharmacologically active form.
28. The method of Cliam 27, wherein said tumor-associated protease is a fibrinolytic enzyme selected from the group consisting of plasmin and plasminogen activator.
29. The method of Claim 27, wherein said reactive site is a free amino group, a free hydroxyl group, or a free sulfhydryl group.
30. The method of Claim 29, wherein said antineoplastic agent is selected from the group consisting of cytosine arabinoside, adriamycin, daunomycin, 6-thioguanine, fluorodeoxyuridine, bis- (2-chloroethyl) amine, phenylenediamine mustard, 3'-aminothymidine,
L-alanosine, 2-aminothiodiazole, l,4-dihydroxy-5,8-bis (2-aminoethylamino) -9, 10-anthracenedione,
31. The method of Claim 27, wherein said derivatization is carried out either directly or through an intermediate self-immolative connector with the C-terminus of said peptide specifier, and the C-terminal amino acid residue of said peptide specifier is a basic amino acid residue.
32. The method of Claim 31, wherein said peptide specifier has an amino acid residue chain length ranging from that of a tripeptide to that of a pentadecapeptide, and its N-terminal amino acid residue is a D-amino acid residue, a protected L-amino acid residue or protected glycine.
33. The method of Claim 32, wherein said peptide specifier contains a hydrophobic amino acid residue or glycine in the position immediately adjacent to said C-terminal amino acid residue.
34. The method of Claim 33, wherein said C-terminal amino acid residue is lysine, said amino acid residue in the position immediately adjacent to said C-terminal amino acid residue is leucine, and said N-terminal amino acid residue is D-valine or D-isoleucine.
35. The method of Claim 33, wherein the amino acid residue sequence in said peptide speci fier substantially mimics the amino acid residue sequence on the carboxyl side of the Arg-Val bond in plasminogen which serves as the site of cleavage of plasminogen by plasminogen activator, with said C-terminal amino acid residue being arginine, and the amino acid residue in the position immediately adjacent to said C-terminal amino acid residue being glycine.
36. The method of Claim 27, wherein the peptide specifier reactant in the derivatization reaction has its C-terminus in the free acid form and all of its other reactive groups suitably blocked with protecting groups, said reactive site is a free amino group or a free hydroxyl group of said antineoplastic agent, said derivatization reaction is carried out directly between said C-terminus of said peptide specifier reactant and said reactive site of said antineoplastic agent, and subsequent to said derivatization reaction said protecting groups are removed from the reaction product.
37. The method of Claim 27, wherein the peptide specifier, reactant in the derivatization reaction has its C-terminus in the free acid form and all of its other reactive groups suitably blocked with protecting groups; said reactive site is a free amino group, a free hydroxyl group or a free sulfhydryl group of said antineoplastic agent; said derivatization reaction is carried out in a multi-step procedure comprising:
(a) reacting said C-terminus of said peptide specifier reactant with the free amino group of a p-aminobenzyl alcohol reactant having the general formula
wherein R1 is hydrogen or one or more substituent groups which are either electron-donating groups or electron-withdrawing groups, and R2 and R3 may be the same or different and are each selected from the group consisting of hydrogen, alkyl, phenyl, and phenyl substituted with either electron-donating groups or electron- withdrawing groups, to obtain a peptidyl benzyl alcohol having the general formula
(b) reacting said peptidyl benzyl alcohol with either phosgene or a chloroformate reagent to convert said peptidyl benzyl alcohol into, respectively, either a peptidyl benzyl chloroformate or a peptidyl benzyl mixed carbonate, and
(c) reacting said peptidyl benzyl chloroformate or peptidyl benzyl mixed carbonate with said reactive site of said antineoplastic agent to obtain a derivatization re action product having the general formula
38. The method of Claim 37, wherein R1 is hydrogen, R2 is hydrogen or methyl, and R3 is hydrogen or methyl.
39. The method of Claim 37, wherein said chloroformate reagent is selected from the group consisting of pentafluorophenyl chloroformate, pentachlorophenyl chloroformate, and p-nitrophenyl chloroformate .
40. In a method for the treatment of neoplastic diseases in an animal or human host which comprises administering to said host in need thereof an antineoplastically effective amount of an antineoplastic agent, the improvement consisting of administering said antineoplastic agent in the form of the peptidyl derivative pro-drug of Claim 1, whereby the selectivity of delivery of said antineoplastic agent to the tumor site of intended action is enhanced.
41. A hydrolytic enzyme-activatible pro-drug having the general formula
wherei R1 is hydrogen or one or more substituent groups which are either electron-donating groups or electron- withdrawing groups; R2 and R3 may be the same or different and are each selected from the group consisting of hydrogen, alkyl, phenyl, and phenyl substituted with either electron-donating groups or electron-withdrawing groups; R4 is NH or O; when R4 is NH, the specifier moiety is selected from the group consisting of a peptide, an amino acid, a carboxylic acid, and phosphoric acid; when R4 is 0, the specifier moiety is selected from the group consisting of a carboxylic acid, phosphoric acid, and sulfuric acid; and the drug moiety is a normally pharmacologically active agent having a reactive site whose derivatization inhibits pharmacological activity, said reactive site being selected from the group consisting of a free amino group, a free hydroxyl group and a free sulfhydryl group, the covalent linkage between said drug moiety and its adjacent carbonyl group being at said reactive site so as to inhibit the pharmacological activity of said drug moiety.
42. The pro-drug of Claim 41, wherein R1 is hydrogen, R2 is hydrogen or methyl, and R3 is hydrogen or methyl.
43. The pro-drug of Claim 41, wherein said drug moiety is an antineoplastic agent.
44. The pro-drug of Claim 41, wherein R. is NH and the specifier moiety is a peptide.
45. The pro-drug of Claim 42, wherein said drug moiety is an antineoplastic agent,R4 is NH and the specifier moiety is a peptide.
46. In a method of converting a pharmacologically active drug into a hydrolytic enzyme- activatible pro-drug by derivatizing said drug at a reactive site thereof appropriate for inhibiting its pharmacological activity, with a specifier designed to be selectively enzymatically cleaved from the resulting pro-drug by a target hydrolytic enzyme so as to effect release of said drug in pharmacologically active form, the improvement consisting of spacing the specifier moiety from the drug moiety by means of an intermediate self- immolative connector moiety covalently linked at its one end to said specifier moiety and covalently linked at its other end to said reactive site of said drug moiety, said intermediate self-immolative connector moiety having a molecular structure such that the drug- activating enzymatic cleavage of the bond covalently linking it to said specifier moiety will initiate spontaneous cleavage of the bond covalently linking it to said drug moiety to thereby effect release of said drug in pharmacologically active form.
47. The method of Claim 46, wherein said reactive site of said drug is selected from the group consisting of a free amino group, a free hydroxyl group, and a free sulfhydryl group,and said specifier is selected from the group consisting of a peptide, an amino acid, a carboxylic acid, phosphoric acid and sulfuric acid.
48. The method of Claim 47, wherein said resulting pro-drug has the general formula
wherein R, is hydrogen or one or more substituent groups which are either electron-donating groups or electron-withdrawing groups; R2 and R3 may be the same or different and are each selected from the group consisting of hydrogen, alkyl, phenyl, and phenyl substituted with either electron-donating groups or electron-withdrawing groups; R4 is NH or 0; when R4 is NH, the specifier moiety is selected from the group consisting of a peptide, an amino acid, a carboxylic acid, and phosphoric acid; and when R4 is O, the specifier moiety is selected from the group consisting of a carboxylic acid, phosphoric acid, and sulfuric acid.
49. The method of Claim 48, wherein the preparation of said pro-drug comprises the.steps of: (a) reacting said specifier with a p- substituted benzyl alcohol reactant having the general formula
wherein R1, R2,R3 and R4 have the same meanings as defined above, to obtain a specifier-benzyl alcohol intermediate derivative having the general formula
(b) reacting said specifier-benzyl alcohol intermediate derivative with either phosgene or a chloroformate reagent to convert said specifier-benzyl alcohol intermediate derivative into, respectively, either a specifier-benzyl chloroformate intermediate derivative or a specifier-benzyl mixed carbonate intermediate derivative; and
(c) reacting said specifier-benzyl chloroformate intermediate derivative or specifier-benzyl mixed carbonate intermediate derivative with said reactive site of said drug to obtain said pro-drug.
50. The method of Claim 49, wherein said chloroformate reagent,.is selected from the group consisting of pentTafluorophenyl chloroformate, penta- chlor^phenyl chϊdroformate, and p-nitrophenyl chloroformate.
51. The method of Claim 49, wherein R1 is hydrogen, R2 is hydrogen or methyl, and R3 is hydrogen or methyl.
52. The method of Claim 49, wherein said drug is an antineoplastic agent.
53. The method of Claim 49, wherein R4 is NH and the specifier is a peptide.
54. The method of Claim 51, wherein said drug is an antineoplastic agent, R4 is NH, and the specifier is a peptide.
55. A pro-drug of a normally pharmacologically active compound comprising a peptidyl derivative of said compound, said peptidyl derivative being a selective substrate for drug-activating enzymatic cleavage for one or more proteases selected from the group consisting of fibrinolytic enzymes and blood- coagulating enzymes.
56. The pro-drug of Claim 55, wherein said protease is a fibrinolytic enzyme selected from the group consisting of plasmin and plasminogen activator
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US8609679A | 1979-10-18 | 1979-10-18 | |
US86096 | 2002-02-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1981001145A1 true WO1981001145A1 (en) | 1981-04-30 |
Family
ID=22196237
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1980/001290 WO1981001145A1 (en) | 1979-10-18 | 1980-10-01 | Hydrolytic enzyme-activatible pro-drugs |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP0038357A4 (en) |
CA (1) | CA1158557A (en) |
WO (1) | WO1981001145A1 (en) |
Cited By (245)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0237082A3 (en) * | 1986-03-14 | 1988-09-14 | Syntex (U.S.A.) Inc. | Transglutaminase inhibitors |
US4912120A (en) * | 1986-03-14 | 1990-03-27 | Syntex (U.S.A.) Inc. | 3,5-substituted 4,5-dihydroisoxazoles as transglutaminase inhibitors |
US4921941A (en) * | 1987-07-01 | 1990-05-01 | Schering Corporation | Orally active antiandrogens |
US4929630A (en) * | 1986-03-14 | 1990-05-29 | Syntex (U.S.A.) Inc. | Transglutaminase inhibitors |
DE4236237A1 (en) * | 1992-10-27 | 1994-04-28 | Behringwerke Ag | Prodrugs, their preparation and use as medicines |
EP0642799A1 (en) * | 1993-09-09 | 1995-03-15 | BEHRINGWERKE Aktiengesellschaft | Improved prodrugs for enzyme mediated activation |
EP0648503A1 (en) * | 1993-09-22 | 1995-04-19 | BEHRINGWERKE Aktiengesellschaft | Pro-prodrugs, their production and use |
WO1996001653A1 (en) * | 1994-07-11 | 1996-01-25 | Board Of Regents, The University Of Texas System | Methods and compositions for the specific coagulation of vasculature |
US5561119A (en) * | 1991-04-30 | 1996-10-01 | Laboratoires Hoechst | Glycosylated prodrugs, their method of preparation and their uses |
US5660827A (en) * | 1992-03-05 | 1997-08-26 | Board Of Regents, The University Of Texas System | Antibodies that bind to endoglin |
US5855866A (en) * | 1992-03-05 | 1999-01-05 | Board Of Regenis, The University Of Texas System | Methods for treating the vasculature of solid tumors |
US5863538A (en) * | 1992-03-05 | 1999-01-26 | Board Of Regents, The University Of Texas System | Compositions for targeting the vasculature of solid tumors |
US5877289A (en) * | 1992-03-05 | 1999-03-02 | The Scripps Research Institute | Tissue factor compositions and ligands for the specific coagulation of vasculature |
US5880131A (en) * | 1993-10-20 | 1999-03-09 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
US5965566A (en) * | 1993-10-20 | 1999-10-12 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
US6004555A (en) * | 1992-03-05 | 1999-12-21 | Board Of Regents, The University Of Texas System | Methods for the specific coagulation of vasculature |
US6036955A (en) * | 1992-03-05 | 2000-03-14 | The Scripps Research Institute | Kits and methods for the specific coagulation of vasculature |
US6093399A (en) * | 1992-03-05 | 2000-07-25 | Board Of Regents, The University Of Texas System | Methods and compositions for the specific coagulation of vasculature |
US6153655A (en) * | 1998-04-17 | 2000-11-28 | Enzon, Inc. | Terminally-branched polymeric linkers and polymeric conjugates containing the same |
US6214345B1 (en) | 1993-05-14 | 2001-04-10 | Bristol-Myers Squibb Co. | Lysosomal enzyme-cleavable antitumor drug conjugates |
WO2002022833A1 (en) * | 2000-09-15 | 2002-03-21 | Universität Stuttgart | Fusion protein from antibody cytokine-cytokine inhibitor (selectokine) for use as target-specific prodrug |
WO2002030463A2 (en) | 2000-10-12 | 2002-04-18 | Genentech, Inc. | Reduced-viscosity concentrated protein formulations |
EP1243276A1 (en) * | 2001-03-23 | 2002-09-25 | Franciscus Marinus Hendrikus De Groot | Elongated and multiple spacers containing activatible prodrugs |
US6511649B1 (en) | 1998-12-18 | 2003-01-28 | Thomas D. Harris | Vitronectin receptor antagonist pharmaceuticals |
US6511648B2 (en) | 1998-12-18 | 2003-01-28 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
US6524553B2 (en) | 1998-03-31 | 2003-02-25 | Bristol-Myers Squibb Pharma Company | Quinolone vitronectin receptor antagonist pharmaceuticals |
US6537520B1 (en) | 1998-03-31 | 2003-03-25 | Bristol-Myers Squibb Pharma Company | Pharmaceuticals for the imaging of angiogenic disorders |
US6548663B1 (en) | 1998-03-31 | 2003-04-15 | Bristol-Myers Squibb Pharma Company | Benzodiazepine vitronectin receptor antagonist pharmaceuticals |
US6558649B1 (en) | 1998-12-18 | 2003-05-06 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
US6569402B1 (en) | 1998-12-18 | 2003-05-27 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
US6749853B1 (en) | 1992-03-05 | 2004-06-15 | Board Of Regents, The University Of Texas System | Combined methods and compositions for coagulation and tumor treatment |
US6794518B1 (en) | 1998-12-18 | 2004-09-21 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
EP1619250A1 (en) | 1996-01-08 | 2006-01-25 | Genentech, Inc. | WSX receptor and ligands |
WO2006009901A2 (en) | 2004-06-18 | 2006-01-26 | Ambrx, Inc. | Novel antigen-binding polypeptides and their uses |
EP1650220A2 (en) | 1997-04-07 | 2006-04-26 | Genentech, Inc. | Anti-VEGF antibodies |
US7037898B2 (en) | 1994-08-19 | 2006-05-02 | Laregion Wallone | Tumor-activated prodrug compounds and treatment |
WO2006074418A2 (en) | 2005-01-07 | 2006-07-13 | Diadexus, Inc. | Ovr110 antibody compositions and methods of use |
WO2006089133A2 (en) | 2005-02-15 | 2006-08-24 | Duke University | Anti-cd19 antibodies and uses in oncology |
US7115573B2 (en) | 2000-06-14 | 2006-10-03 | Medarex, Inc. | Prodrug compounds with an isoleucine |
US7173115B2 (en) | 2000-01-13 | 2007-02-06 | Genentech, Inc. | Stra6 polypeptides |
WO2008011081A2 (en) | 2006-07-19 | 2008-01-24 | The Trustees Of The University Of Pennsylvania | Wsx-1/p28 as a target for anti-inflammatory responses |
EP1950300A2 (en) | 1998-11-18 | 2008-07-30 | Genentech, Inc. | Antibody variants with higher binding affinity compared to parent antibodies |
US7446196B2 (en) | 2004-06-03 | 2008-11-04 | Kosan Biosciences, Incorporated | Leptomycin compounds |
EP1992643A2 (en) | 2001-06-20 | 2008-11-19 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
EP2011886A2 (en) | 2002-04-16 | 2009-01-07 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
EP2014303A2 (en) | 2000-07-27 | 2009-01-14 | Genentech, Inc. | APO-2L receptor agonist and CPT-11 synergism |
WO2009028158A1 (en) | 2007-08-24 | 2009-03-05 | Oncotherapy Science, Inc. | Dkk1 oncogene as therapeutic target for cancer and a diagnosing marker |
EP2042517A1 (en) | 2002-09-27 | 2009-04-01 | Xencor, Inc. | Optimized FC variants and methods for their generation |
EP2052742A1 (en) | 2000-06-20 | 2009-04-29 | Biogen Idec Inc. | Treatment of B-cell associated diseases such as malignancies and autoimmune diseases using a cold anti-CD20 antibody/radiolabeled anti-CD22 antibody combination |
EP2058334A2 (en) | 1998-06-12 | 2009-05-13 | Genentech, Inc. | Monoclonal antibodies, cross-reactive antibodies and method for producing the same |
EP2062591A1 (en) | 2005-04-07 | 2009-05-27 | Novartis Vaccines and Diagnostics, Inc. | CACNA1E in cancer diagnosis detection and treatment |
EP2062916A2 (en) | 2003-04-09 | 2009-05-27 | Genentech, Inc. | Therapy of autoimmune disease in a patient with an inadequate response to a TNF-Alpha inhibitor |
US7541330B2 (en) | 2004-06-15 | 2009-06-02 | Kosan Biosciences Incorporated | Conjugates with reduced adverse systemic effects |
EP2065467A2 (en) | 2001-02-22 | 2009-06-03 | Genentech, Inc. | Anti-interferon-alpha antibodies |
EP2067472A1 (en) | 2002-01-02 | 2009-06-10 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
EP2083088A2 (en) | 2005-04-07 | 2009-07-29 | Novartis Vaccines and Diagnostics, Inc. | Cancer-related genes |
EP2110138A1 (en) | 1999-08-27 | 2009-10-21 | Genentech, Inc. | Dosages for treatment of anti-erbB2 antibodies |
EP2112167A2 (en) | 1999-06-25 | 2009-10-28 | Genentech, Inc. | Humanized ANTI-ERBB2 antibodies and treatment with ANTI-ERBB2 antibodies |
WO2010001585A1 (en) | 2008-06-30 | 2010-01-07 | Oncotherapy Science, Inc. | Anti-cdh3 antibodies labeled with radioisotope label and uses thereof |
EP2143438A1 (en) | 2001-09-18 | 2010-01-13 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
EP2161283A1 (en) | 2003-11-17 | 2010-03-10 | Genentech, Inc. | Compositions comprising antibodies against CD79b conjugated to a growth inhibitory agent or cytotoxic agent and methods for the treatment of tumor of hematopoietic origin |
WO2010056804A1 (en) | 2008-11-12 | 2010-05-20 | Medimmune, Llc | Antibody formulation |
WO2010060920A1 (en) | 2008-11-27 | 2010-06-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Cxcl4l1 as a biomarker of pancreatic cancer |
WO2010077634A1 (en) | 2008-12-09 | 2010-07-08 | Genentech, Inc. | Anti-pd-l1 antibodies and their use to enhance t-cell function |
EP2221316A1 (en) | 2005-05-05 | 2010-08-25 | Duke University | Anti-CD19 antibody therapy for autoimmune disease |
WO2010102175A1 (en) | 2009-03-05 | 2010-09-10 | Medarex, Inc. | Fully human antibodies specific to cadm1 |
WO2010120561A1 (en) | 2009-04-01 | 2010-10-21 | Genentech, Inc. | Anti-fcrh5 antibodies and immunoconjugates and methods of use |
EP2248829A1 (en) | 2003-05-30 | 2010-11-10 | Genentech, Inc. | Treatment with anti-VEGF antibodies |
EP2263691A1 (en) | 2002-07-15 | 2010-12-22 | Genentech, Inc. | Treatment of cancer with the recombinant humanized monoclonal anti-erbb2 antibody 2C4 (rhuMAb 2C4) |
WO2011017249A1 (en) | 2009-08-03 | 2011-02-10 | Medarex, Inc. | Antiproliferative compounds, conjugates thereof, methods therefor, and uses thereof |
WO2011031397A1 (en) | 2009-08-06 | 2011-03-17 | Genentech, Inc. | Method to improve virus removal in protein purification |
EP2301580A1 (en) | 1997-04-07 | 2011-03-30 | Genentech, Inc. | Anti-VEGF antibodies |
WO2011038302A2 (en) | 2009-09-25 | 2011-03-31 | Xoma Technology Ltd. | Novel modulators |
WO2011038301A2 (en) | 2009-09-25 | 2011-03-31 | Xoma Technology Ltd. | Screening methods |
EP2311873A1 (en) | 2004-01-07 | 2011-04-20 | Novartis Vaccines and Diagnostics, Inc. | M-CSF-specific monoclonal antibody and uses thereof |
WO2011050194A1 (en) | 2009-10-22 | 2011-04-28 | Genentech, Inc. | Methods and compositions for modulating hepsin activation of macrophage-stimulating protein |
WO2011066503A2 (en) | 2009-11-30 | 2011-06-03 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
EP2333069A2 (en) | 1998-05-15 | 2011-06-15 | Genentech, Inc. | Therapeutic uses of IL-17 homologous polypeptides |
EP2335725A1 (en) | 2003-04-04 | 2011-06-22 | Genentech, Inc. | High concentration antibody and protein formulations |
WO2011076922A1 (en) | 2009-12-23 | 2011-06-30 | Synimmune Gmbh | Anti-flt3 antibodies and methods of using the same |
US7982012B2 (en) | 2008-03-10 | 2011-07-19 | Theraclone Sciences, Inc. | Compositions and methods for the therapy and diagnosis of cytomegalovirus |
WO2011089211A1 (en) | 2010-01-22 | 2011-07-28 | Synimmune Gmbh | Anti-cd133 antibodies and methods of using the same |
WO2011104604A2 (en) | 2010-02-23 | 2011-09-01 | Glenmark Pharmaceuticals S.A. | Anti-alpha2 integrin antibodies and their uses |
WO2011106297A2 (en) | 2010-02-23 | 2011-09-01 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
EP2368911A1 (en) | 2003-05-02 | 2011-09-28 | Xencor Inc. | Optimized Fc variants and methods for their generation |
US8029783B2 (en) | 2005-02-02 | 2011-10-04 | Genentech, Inc. | DR5 antibodies and articles of manufacture containing same |
EP2383297A1 (en) | 2006-08-14 | 2011-11-02 | Xencor Inc. | Optimized antibodies that target CD19 |
WO2011139985A1 (en) | 2010-05-03 | 2011-11-10 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
US8057796B2 (en) | 2007-11-12 | 2011-11-15 | Theraclone Sciences, Inc. | Compositions and methods for the therapy and diagnosis of influenza |
EP2386640A2 (en) | 2004-08-26 | 2011-11-16 | EnGeneIC Molecular Delivery Pty Ltd | Delivering functional nucleic acids to mammalian cells via bacterially-derived, intact minicells |
US8063187B2 (en) | 2007-05-30 | 2011-11-22 | Xencor, Inc. | Methods and compositions for inhibiting CD32B expressing cells |
WO2011145068A1 (en) | 2010-05-20 | 2011-11-24 | Centre National De La Recherche Scientifique | Novel self-reactive arms and prodrugs comprising same |
EP2389948A1 (en) | 2006-03-23 | 2011-11-30 | Novartis AG | Anti-tumor cell antigen antibody therapeutics |
EP2407483A1 (en) | 2006-04-13 | 2012-01-18 | Novartis Vaccines and Diagnostics, Inc. | Methods of treating, diagnosing or detecting cancers |
EP2423333A1 (en) | 2006-08-25 | 2012-02-29 | Oncotherapy Science, Inc. | Prognostic markers and therapeutic targets for lung cancer |
EP2423231A2 (en) | 2006-08-18 | 2012-02-29 | Novartis AG | PRLR-specific antibody and uses thereof |
EP2447372A2 (en) | 2005-07-08 | 2012-05-02 | Biogen Idec MA Inc. | Anti alpha v beta 6 antibodies and uses thereof |
WO2012061448A1 (en) | 2010-11-04 | 2012-05-10 | Boehringer Ingelheim International Gmbh | Anti-il-23 antibodies |
WO2012085111A1 (en) | 2010-12-23 | 2012-06-28 | F. Hoffmann-La Roche Ag | Polypeptide-polynucleotide-complex and its use in targeted effector moiety delivery |
EP2471813A1 (en) | 2004-07-15 | 2012-07-04 | Xencor Inc. | Optimized Fc variants |
EP2474557A2 (en) | 2007-07-16 | 2012-07-11 | Genentech, Inc. | Anti-CD79b antibodies and immunoconjugates and methods of use |
EP2474556A2 (en) | 2007-03-14 | 2012-07-11 | Novartis AG | APCDD1 inhibitors for treating, diagnosing or detecting cancer |
US8236315B2 (en) | 2008-01-23 | 2012-08-07 | Glenmark Pharmaceuticals, S.A. | Humanized antibodies specific for von Willebrand factor |
WO2012109624A2 (en) | 2011-02-11 | 2012-08-16 | Zyngenia, Inc. | Monovalent and multivalent multispecific complexes and uses thereof |
WO2012118813A2 (en) | 2011-03-03 | 2012-09-07 | Apexigen, Inc. | Anti-il-6 receptor antibodies and methods of use |
WO2012122513A2 (en) | 2011-03-10 | 2012-09-13 | Omeros Corporation | Generation of anti-fn14 monoclonal antibodies by ex-vivo accelerated antibody evolution |
US8268970B2 (en) | 2007-10-01 | 2012-09-18 | Bristol-Myers Squibb Company | Human antibodies that bind mesothelin, and uses thereof |
WO2012125614A1 (en) | 2011-03-15 | 2012-09-20 | Theraclone Sciences, Inc. | Compositions and methods for the therapy and diagnosis of influenza |
US8278421B2 (en) | 2006-03-20 | 2012-10-02 | Xoma Techolology Ltd. | Human antibodies specific for gastrin materials and methods |
US8298531B2 (en) | 2008-11-06 | 2012-10-30 | Glenmark Pharmaceuticals, S.A. | Treatment with anti-alpha2 integrin antibodies |
WO2012149356A2 (en) | 2011-04-29 | 2012-11-01 | Apexigen, Inc. | Anti-cd40 antibodies and methods of use |
WO2012162561A2 (en) | 2011-05-24 | 2012-11-29 | Zyngenia, Inc. | Multivalent and monovalent multispecific complexes and their uses |
WO2012167143A1 (en) | 2011-06-03 | 2012-12-06 | Xoma Technology Ltd. | Antibodies specific for tgf-beta |
EP2532746A2 (en) | 2007-03-30 | 2012-12-12 | EnGeneIC Molecular Delivery Pty Ltd. | Bacterially-derived, intact minicells that encompass plasmid-free functional nucleic acid for in vivo delivery to mammalian cells |
EP2540741A1 (en) | 2006-03-06 | 2013-01-02 | Aeres Biomedical Limited | Humanized anti-CD22 antibodies and their use in treatment of oncology, transplantation and autoimmune disease |
WO2013033069A1 (en) | 2011-08-30 | 2013-03-07 | Theraclone Sciences, Inc. | Human rhinovirus (hrv) antibodies |
WO2013063001A1 (en) | 2011-10-28 | 2013-05-02 | Genentech, Inc. | Therapeutic combinations and methods of treating melanoma |
WO2013067098A1 (en) | 2011-11-02 | 2013-05-10 | Apexigen, Inc. | Anti-kdr antibodies and methods of use |
WO2013074569A1 (en) | 2011-11-16 | 2013-05-23 | Boehringer Ingelheim International Gmbh | Anti il-36r antibodies |
WO2013101771A2 (en) | 2011-12-30 | 2013-07-04 | Genentech, Inc. | Compositions and method for treating autoimmune diseases |
EP2614839A2 (en) | 2006-04-05 | 2013-07-17 | Genentech, Inc. | Method for using BOC/CDO to modulate hedgehog signaling |
WO2013116287A1 (en) | 2012-01-31 | 2013-08-08 | Genentech, Inc. | Anti-ig-e m1' antibodies and methods using same |
WO2013122823A1 (en) | 2012-02-13 | 2013-08-22 | Bristol-Myers Squibb Company | Enediyne compounds, conjugates thereof, and uses and methods therefor |
EP2641618A2 (en) | 2007-07-16 | 2013-09-25 | Genentech, Inc. | Humanized anti-CD79B antibodies and immunoconjugates and methods of use |
WO2013149159A1 (en) | 2012-03-30 | 2013-10-03 | Genentech, Inc. | Anti-lgr5 antibodies and immunoconjugates |
EP2657253A2 (en) | 2008-01-31 | 2013-10-30 | Genentech, Inc. | Anti-CD79b antibodies and immunoconjugates and methods of use |
WO2013165791A1 (en) | 2012-05-03 | 2013-11-07 | Boehringer Ingelheim International Gmbh | Anti-il-23p19 antibodies |
WO2013165940A1 (en) | 2012-05-01 | 2013-11-07 | Genentech, Inc. | Anti-pmel17 antibodies and immunoconjugates |
US8586716B2 (en) | 2006-08-04 | 2013-11-19 | Novartis Ag | EPHB3-specific antibody and uses thereof |
US8591862B2 (en) | 2006-06-23 | 2013-11-26 | Engeneic Molecular Delivery Pty Ltd | Targeted delivery of drugs, therapeutic nucleic acids and functional nucleic acids to mammalian cells via intact killed bacterial cells |
WO2013185114A2 (en) | 2012-06-08 | 2013-12-12 | Biogen Idec Ma Inc. | Chimeric clotting factors |
US8609101B2 (en) | 2009-04-23 | 2013-12-17 | Theraclone Sciences, Inc. | Granulocyte-macrophage colony-stimulating factor (GM-CSF) neutralizing antibodies |
USRE44681E1 (en) | 2006-07-10 | 2013-12-31 | Biogen Idec Ma Inc. | Compositions and methods for inhibiting growth of SMAD4-deficient cancers |
US8652469B2 (en) | 2005-07-28 | 2014-02-18 | Novartis Ag | M-CSF-specific monoclonal antibody and uses thereof |
WO2014027959A1 (en) | 2012-08-14 | 2014-02-20 | Nanyang Technological University | Angiopoietin-like 4 antibody and a method of its use in cancer treatment |
EP2703011A2 (en) | 2007-05-07 | 2014-03-05 | MedImmune, LLC | Anti-icos antibodies and their use in treatment of oncology, transplantation and autoimmune disease |
WO2014047199A1 (en) * | 2012-09-19 | 2014-03-27 | The Research Foundation For The State University Of New York | Novel prodrugs for selective anticancer therapy |
WO2014079886A1 (en) | 2012-11-20 | 2014-05-30 | Sanofi | Anti-ceacam5 antibodies and uses thereof |
WO2014126836A1 (en) | 2013-02-14 | 2014-08-21 | Bristol-Myers Squibb Company | Tubulysin compounds, methods of making and use |
WO2014159835A1 (en) | 2013-03-14 | 2014-10-02 | Genentech, Inc. | Anti-b7-h4 antibodies and immunoconjugates |
US8852586B2 (en) | 2004-11-12 | 2014-10-07 | Xencor, Inc. | Fc variants with altered binding to FcRn |
US8858948B2 (en) | 2009-05-20 | 2014-10-14 | Theraclone Sciences, Inc. | Compositions and methods for the therapy and diagnosis of influenza |
US8865875B2 (en) | 2007-08-22 | 2014-10-21 | Medarex, L.L.C. | Site-specific attachment of drugs or other agents to engineered antibodies with C-terminal extensions |
EP2796467A1 (en) | 2010-03-31 | 2014-10-29 | Boehringer Ingelheim International GmbH | Anti-CD40 antibodies |
US8900590B2 (en) | 2010-08-12 | 2014-12-02 | Theraclone Sciences, Inc. | Anti-hemagglutinin antibody compositions and methods of use thereof |
US8916160B2 (en) | 2011-02-14 | 2014-12-23 | Theraclone Sciences, Inc. | Compositions and methods for the therapy and diagnosis of influenza |
US8937158B2 (en) | 2003-03-03 | 2015-01-20 | Xencor, Inc. | Fc variants with increased affinity for FcγRIIc |
WO2015023596A1 (en) | 2013-08-12 | 2015-02-19 | Genentech, Inc. | Compositions and method for treating complement-associated conditions |
WO2015042108A1 (en) | 2013-09-17 | 2015-03-26 | Genentech, Inc. | Methods of using anti-lgr5 antibodies |
US9000132B2 (en) | 2013-03-15 | 2015-04-07 | Diadexus, Inc. | Lipoprotein-associated phospholipase A2 antibody compositions and methods of use |
EP2857516A1 (en) | 2000-04-11 | 2015-04-08 | Genentech, Inc. | Multivalent antibodies and uses therefor |
US9040041B2 (en) | 2005-10-03 | 2015-05-26 | Xencor, Inc. | Modified FC molecules |
WO2015089344A1 (en) | 2013-12-13 | 2015-06-18 | Genentech, Inc. | Anti-cd33 antibodies and immunoconjugates |
WO2015095227A2 (en) | 2013-12-16 | 2015-06-25 | Genentech, Inc. | Peptidomimetic compounds and antibody-drug conjugates thereof |
US9085621B2 (en) | 2010-09-10 | 2015-07-21 | Apexigen, Inc. | Anti-IL-1β antibodies |
WO2015112909A1 (en) | 2014-01-24 | 2015-07-30 | Genentech, Inc. | Methods of using anti-steap1 antibodies and immunoconjugates |
EP2926830A2 (en) | 2010-08-31 | 2015-10-07 | Theraclone Sciences, Inc. | Human immunodeficiency virus (HIV)-neutralizing antibodies |
WO2015179658A2 (en) | 2014-05-22 | 2015-11-26 | Genentech, Inc. | Anti-gpc3 antibodies and immunoconjugates |
US9200079B2 (en) | 2004-11-12 | 2015-12-01 | Xencor, Inc. | Fc variants with altered binding to FcRn |
EP2962697A1 (en) | 2006-11-27 | 2016-01-06 | diaDexus, Inc. | Ovr110 antibody compositions and methods of use |
US9260517B2 (en) | 2009-11-17 | 2016-02-16 | Musc Foundation For Research Development | Human monoclonal antibodies to human nucleolin |
US9278131B2 (en) | 2012-08-10 | 2016-03-08 | Adocia | Process for lowering the viscosity of highly concentrated protein solutions |
WO2016039801A1 (en) | 2014-01-31 | 2016-03-17 | Boehringer Ingelheim International Gmbh | Novel anti-baff antibodies |
WO2016040868A1 (en) | 2014-09-12 | 2016-03-17 | Genentech, Inc. | Anti-cll-1 antibodies and immunoconjugates |
WO2016077260A1 (en) | 2014-11-10 | 2016-05-19 | Bristol-Myers Squibb Company | Tubulysin analogs and methods of making and use |
EP3023497A1 (en) | 2005-11-18 | 2016-05-25 | Glenmark Pharmaceuticals S.A. | Anti-alpha2 integrin antibodies and their uses |
WO2016115201A1 (en) | 2015-01-14 | 2016-07-21 | Bristol-Myers Squibb Company | Heteroarylene-bridged benzodiazepine dimers, conjugates thereof, and methods of making and using |
WO2016141111A1 (en) | 2015-03-03 | 2016-09-09 | Xoma (Us) Llc | Treatment of post-prandial hyperinsulinemia and hypoglycemia after bariatric surgery |
WO2016161410A2 (en) | 2015-04-03 | 2016-10-06 | Xoma Technology Ltd. | Treatment of cancer using inhibitors of tgf-beta and pd-1 |
US9465029B2 (en) | 2004-04-16 | 2016-10-11 | Glaxo Group Limited | Methods for detecting LP-PLA2 activity and inhibition of LP-PLA2 activity |
EP3095463A2 (en) | 2008-09-16 | 2016-11-23 | F. Hoffmann-La Roche AG | Methods for treating progressive multiple sclerosis |
WO2016196381A1 (en) | 2015-05-29 | 2016-12-08 | Genentech, Inc. | Pd-l1 promoter methylation in cancer |
EP3112468A1 (en) | 1998-05-15 | 2017-01-04 | Genentech, Inc. | Il-17 homologous polypeptides and therapeutic uses thereof |
US9562099B2 (en) | 2013-03-14 | 2017-02-07 | Genentech, Inc. | Anti-B7-H4 antibodies and immunoconjugates |
EP3130349A1 (en) | 2004-06-04 | 2017-02-15 | Genentech, Inc. | Method for treating multiple sclerosis |
WO2017062682A2 (en) | 2015-10-06 | 2017-04-13 | Genentech, Inc. | Method for treating multiple sclerosis |
US9714282B2 (en) | 2003-09-26 | 2017-07-25 | Xencor, Inc. | Optimized Fc variants and methods for their generation |
EP3208281A1 (en) | 2010-03-29 | 2017-08-23 | Zymeworks, Inc. | Antibodies with enhanced or suppressed effector function |
US9745376B2 (en) | 2002-03-13 | 2017-08-29 | Biogen Ma Inc. | Anti-ανβ6 antibodies |
US9809653B2 (en) | 2012-12-27 | 2017-11-07 | Sanofi | Anti-LAMP1 antibodies and antibody drug conjugates, and uses thereof |
WO2017194568A1 (en) | 2016-05-11 | 2017-11-16 | Sanofi | Treatment regimen using anti-muc1 maytansinoid immunoconjugate antibody for the treatment of tumors |
WO2017197234A1 (en) | 2016-05-13 | 2017-11-16 | Bioatla, Llc | Anti-ror2 antibodies, antibody fragments, their immunoconjugates and uses thereof |
WO2017214452A1 (en) | 2016-06-08 | 2017-12-14 | Xencor, Inc. | Treatment of igg4-related diseases with anti-cd19 antibodies crossbinding to cd32b |
EP3260136A1 (en) | 2009-03-17 | 2017-12-27 | Theraclone Sciences, Inc. | Human immunodeficiency virus (hiv) -neutralizing antibodies |
WO2018026748A1 (en) | 2016-08-01 | 2018-02-08 | Xoma (Us) Llc | Parathyroid hormone receptor 1 (pth1r) antibodies and uses thereof |
WO2018035391A1 (en) | 2016-08-19 | 2018-02-22 | Bristol-Myers Squibb Company | Seco-cyclopropapyrroloindole compounds, antibody-drug conjugates thereof, and methods of making and use |
WO2018075842A1 (en) | 2016-10-20 | 2018-04-26 | Bristol-Myers Squibb Company | Condensed benzodiazepine derivatives and conjugates made therefrom |
WO2018091724A1 (en) | 2016-11-21 | 2018-05-24 | Cureab Gmbh | Anti-gp73 antibodies and immunoconjugates |
WO2018134412A1 (en) * | 2017-01-20 | 2018-07-26 | Biosynth Ag | Antimicrobial compounds and uses thereof |
US10035860B2 (en) | 2013-03-15 | 2018-07-31 | Biogen Ma Inc. | Anti-alpha V beta 6 antibodies and uses thereof |
US10035859B2 (en) | 2013-03-15 | 2018-07-31 | Biogen Ma Inc. | Anti-alpha V beta 6 antibodies and uses thereof |
US10059768B2 (en) | 2014-09-12 | 2018-08-28 | Genentech, Inc. | Anti-B7-H4 antibodies and immunoconjugates |
WO2018183173A1 (en) | 2017-03-27 | 2018-10-04 | Boehringer Ingelheim International Gmbh | Anti il-36r antibodies combination therapy |
EP3392274A1 (en) | 2011-08-12 | 2018-10-24 | Omeros Corporation | Anti-fzd10 monoclonal antibodies and methods for their use |
WO2019036023A1 (en) | 2017-08-16 | 2019-02-21 | Bristol-Myers Squibb Company | 6-amino-7,9-dihydro-8h-purin-8-one derivatives as immunostimulant toll-like receptor 7 (tlr7) agonists |
WO2019035970A1 (en) | 2017-08-16 | 2019-02-21 | Bristol-Myers Squibb Company | 6-amino-7,9-dihydro-8h-purin-8-one derivatives as immunostimulant toll-like receptor 7 (tlr7) agonists |
WO2019035969A1 (en) | 2017-08-16 | 2019-02-21 | Bristol-Myers Squibb Company | Toll-like receptor 7 (tlr7) agonists having a tricyclic moiety, conjugates thereof, and methods and uses therefor |
WO2019035971A1 (en) | 2017-08-16 | 2019-02-21 | Bristol-Myers Squibb Company | 6-amino-7,9-dihydro-8h-purin-8-one derivatives as immunostimulant toll-like receptor 7 (tlr7) agonists |
WO2019035968A1 (en) | 2017-08-16 | 2019-02-21 | Bristol-Myers Squibb Company | 6-amino-7,9-dihydro-8h-purin-8-one derivatives as toll-like receptor 7 (tlr7) agonists as immunostimulants |
EP3450459A2 (en) | 2009-12-28 | 2019-03-06 | OncoTherapy Science, Inc. | Anti-cdh3 antibodies and uses thereof |
US10253101B2 (en) | 2015-08-06 | 2019-04-09 | Xoma (Us) Llc | Antibody fragments against the insulin receptor and uses thereof to treat hypoglycemia |
US10287564B2 (en) | 2012-06-08 | 2019-05-14 | Bioverativ Therapeutics Inc. | Procoagulant compounds |
WO2019209811A1 (en) | 2018-04-24 | 2019-10-31 | Bristol-Myers Squibb Company | Macrocyclic toll-like receptor 7 (tlr7) agonists |
WO2019231879A1 (en) | 2018-05-29 | 2019-12-05 | Bristol-Myers Squibb Company | Modified self-immolating moieties for use in prodrugs and conjugates and methods of using and making |
WO2020006347A1 (en) | 2018-06-29 | 2020-01-02 | Boehringer Ingelheim International Gmbh | Anti-cd40 antibodies for use in treating autoimmune disease |
WO2020028610A1 (en) | 2018-08-03 | 2020-02-06 | Bristol-Myers Squibb Company | 2H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS AND METHODS AND USES THEREFOR |
EP3653641A1 (en) | 2004-02-19 | 2020-05-20 | Genentech, Inc. | Cdr-repaired antibodies |
WO2020117257A1 (en) | 2018-12-06 | 2020-06-11 | Genentech, Inc. | Combination therapy of diffuse large b-cell lymphoma comprising an anti-cd79b immunoconjugates, an alkylating agent and an anti-cd20 antibody |
EP3689910A2 (en) | 2014-09-23 | 2020-08-05 | F. Hoffmann-La Roche AG | Method of using anti-cd79b immunoconjugates |
EP3693023A1 (en) | 2019-02-11 | 2020-08-12 | Sanofi | Use of anti-ceacam5 immunoconjugates for treating lung cancer |
WO2020161214A1 (en) | 2019-02-07 | 2020-08-13 | Sanofi | Use of anti-ceacam5 immunoconjugates for treating lung cancer |
EP3576727A4 (en) * | 2017-02-01 | 2020-09-09 | The Johns Hopkins University | Prodrugs of glutamine analogs |
WO2020191377A1 (en) | 2019-03-21 | 2020-09-24 | Codiak Biosciences, Inc. | Extracellular vesicle conjugates and uses thereof |
WO2020232169A1 (en) | 2019-05-14 | 2020-11-19 | Genentech, Inc. | Methods of using anti-cd79b immunoconjugates to treat follicular lymphoma |
WO2021023658A1 (en) | 2019-08-02 | 2021-02-11 | Immatics Biotechnologies Gmbh | Antigen binding proteins specifically binding mage-a |
WO2021023657A1 (en) | 2019-08-02 | 2021-02-11 | Immatics Biotechnologies Gmbh | Modified bi specific anti cd3 antibodies |
WO2021030777A1 (en) | 2019-08-14 | 2021-02-18 | Codiak Biosciences, Inc. | Extracellular vesicle linked to molecules and uses thereof |
WO2021030780A1 (en) | 2019-08-14 | 2021-02-18 | Codiak Biosciences, Inc. | Extracellular vesicle-aso constructs targeting cebp/beta |
WO2021030776A1 (en) | 2019-08-14 | 2021-02-18 | Codiak Biosciences, Inc. | Extracellular vesicle-aso constructs targeting stat6 |
WO2021030773A1 (en) | 2019-08-14 | 2021-02-18 | Codiak Biosciences, Inc. | Extracellular vesicle-nlrp3 antagonist |
WO2021030769A1 (en) | 2019-08-14 | 2021-02-18 | Codiak Biosciences, Inc. | Extracellular vesicles with nras antisense oligonucleotides |
WO2021030781A1 (en) | 2019-08-14 | 2021-02-18 | Codiak Biosciences, Inc. | Extracellular vesicles with antisense oligonucleotides targeting kras |
EP3782654A1 (en) | 2014-09-12 | 2021-02-24 | Genentech, Inc. | Anti-her2 antibodies and immunoconjugates |
WO2021076196A1 (en) | 2019-10-18 | 2021-04-22 | Genentech, Inc. | Methods of using anti-cd79b immunoconjugates to treat diffuse large b-cell lymphoma |
WO2021144020A1 (en) | 2020-01-15 | 2021-07-22 | Immatics Biotechnologies Gmbh | Antigen binding proteins specifically binding prame |
WO2021174034A1 (en) | 2020-02-28 | 2021-09-02 | Genzyme Corporation | Modified binding polypeptides for optimized drug conjugation |
US11149088B2 (en) | 2016-04-15 | 2021-10-19 | Bioatla, Inc. | Anti-Axl antibodies, antibody fragments and their immunoconjugates and uses thereof |
WO2021217051A1 (en) | 2020-04-24 | 2021-10-28 | Genentech, Inc. | Methods of using anti-cd79b immunoconjugates |
EP3925977A1 (en) | 2012-10-30 | 2021-12-22 | Apexigen, Inc. | Anti-cd40 antibodies and methods of use |
WO2022048883A1 (en) | 2020-09-04 | 2022-03-10 | Merck Patent Gmbh | Anti-ceacam5 antibodies and conjugates and uses thereof |
US11357849B2 (en) | 2016-03-07 | 2022-06-14 | Musc Foundation For Research Development | Anti-nucleolin antibodies |
WO2022147463A2 (en) | 2020-12-31 | 2022-07-07 | Alamar Biosciences, Inc. | Binder molecules with high affinity and/ or specificity and methods of making and use thereof |
US11401348B2 (en) | 2009-09-02 | 2022-08-02 | Xencor, Inc. | Heterodimeric Fc variants |
WO2022170008A2 (en) | 2021-02-05 | 2022-08-11 | Boehringer Ingelheim International Gmbh | Anti-il1rap antibodies |
WO2022178180A1 (en) | 2021-02-17 | 2022-08-25 | Codiak Biosciences, Inc. | Extracellular vesicle linked to a biologically active molecule via an optimized linker and an anchoring moiety |
WO2022233956A1 (en) | 2021-05-05 | 2022-11-10 | Immatics Biotechnologies Gmbh | Antigen binding proteins specifically binding prame |
WO2022241446A1 (en) | 2021-05-12 | 2022-11-17 | Genentech, Inc. | Methods of using anti-cd79b immunoconjugates to treat diffuse large b-cell lymphoma |
WO2023006828A1 (en) | 2021-07-27 | 2023-02-02 | Immatics Biotechnologies Gmbh | Antigen binding proteins specifically binding ct45 |
WO2023019092A1 (en) | 2021-08-07 | 2023-02-16 | Genentech, Inc. | Methods of using anti-cd79b immunoconjugates to treat diffuse large b-cell lymphoma |
US11584927B2 (en) | 2014-08-28 | 2023-02-21 | Bioatla, Inc. | Conditionally active chimeric antigen receptors for modified T-cells |
WO2023099682A1 (en) | 2021-12-02 | 2023-06-08 | Sanofi | Ceacam5 adc–anti-pd1/pd-l1 combination therapy |
WO2023099683A1 (en) | 2021-12-02 | 2023-06-08 | Sanofi | Cea assay for patient selection in cancer therapy |
WO2023172968A1 (en) | 2022-03-09 | 2023-09-14 | Merck Patent Gmbh | Anti-gd2 antibodies, immunoconjugates and therapeutic uses thereof |
WO2023170239A1 (en) | 2022-03-09 | 2023-09-14 | Merck Patent Gmbh | Methods and tools for conjugation to antibodies |
US11932685B2 (en) | 2007-10-31 | 2024-03-19 | Xencor, Inc. | Fc variants with altered binding to FcRn |
Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4009264A (en) * | 1975-03-03 | 1977-02-22 | Meito Sangyo Kabushiki Kaisha | Complexes of polysaccharides or derivatives thereof with reduced glutathione and process for preparing said complexes |
US4016146A (en) * | 1974-12-10 | 1977-04-05 | Biological Developments, Inc. | Phenethylamine antigenic conjugates, their preparation, antibodies, and use |
US4039519A (en) * | 1975-04-14 | 1977-08-02 | Chimie & Biologie | Broad spectrum antibiotics and method |
US4057685A (en) * | 1972-02-02 | 1977-11-08 | Abbott Laboratories | Chemically modified endotoxin immunizing agent |
US4119589A (en) * | 1976-01-29 | 1978-10-10 | Boehringer Mannheim Gmbh | Process for fixing proteins onto carriers |
US4123519A (en) * | 1976-08-17 | 1978-10-31 | Philips Roxane, Inc. | Injectable contraceptive vaccine and method |
US4140679A (en) * | 1976-10-12 | 1979-02-20 | Research Corporation | Antigen-protein complex for blocking allergic reactions |
US4150105A (en) * | 1974-11-29 | 1979-04-17 | Biological Developments, Inc. | 3-Ketosteroid antigenic conjugates, their preparation, antibodies and use |
US4192799A (en) * | 1977-09-21 | 1980-03-11 | The Upjohn Company | Conjugates formed by reacting a prostaglandin mimic compound with a carrier molecule |
US4193982A (en) * | 1975-12-05 | 1980-03-18 | Etablissement Declare D'utilite Publique Dit: Institut Pasteur | Process for coupling biological substances by covalent bonds |
US4201770A (en) * | 1973-05-07 | 1980-05-06 | The Ohio State University | Antigenic modification of polypeptides |
US4223013A (en) * | 1978-12-29 | 1980-09-16 | Syva Company | Amitriptyline conjugates to antigenic proteins and enzymes |
US4238389A (en) * | 1979-02-12 | 1980-12-09 | Syva Company | Valproate conjugation using dicarbonyls |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH494208A (en) * | 1967-09-13 | 1970-07-31 | Sandoz Ag | Cytostatically active p-phenylene diamine - derivatives for cancer therapy |
-
1980
- 1980-10-01 WO PCT/US1980/001290 patent/WO1981001145A1/en not_active Application Discontinuation
- 1980-10-15 CA CA000362379A patent/CA1158557A/en not_active Expired
-
1981
- 1981-05-04 EP EP19800902253 patent/EP0038357A4/en not_active Ceased
Patent Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4057685A (en) * | 1972-02-02 | 1977-11-08 | Abbott Laboratories | Chemically modified endotoxin immunizing agent |
US4201770A (en) * | 1973-05-07 | 1980-05-06 | The Ohio State University | Antigenic modification of polypeptides |
US4150105A (en) * | 1974-11-29 | 1979-04-17 | Biological Developments, Inc. | 3-Ketosteroid antigenic conjugates, their preparation, antibodies and use |
US4016146A (en) * | 1974-12-10 | 1977-04-05 | Biological Developments, Inc. | Phenethylamine antigenic conjugates, their preparation, antibodies, and use |
US4009264A (en) * | 1975-03-03 | 1977-02-22 | Meito Sangyo Kabushiki Kaisha | Complexes of polysaccharides or derivatives thereof with reduced glutathione and process for preparing said complexes |
US4039519A (en) * | 1975-04-14 | 1977-08-02 | Chimie & Biologie | Broad spectrum antibiotics and method |
US4193982A (en) * | 1975-12-05 | 1980-03-18 | Etablissement Declare D'utilite Publique Dit: Institut Pasteur | Process for coupling biological substances by covalent bonds |
US4119589A (en) * | 1976-01-29 | 1978-10-10 | Boehringer Mannheim Gmbh | Process for fixing proteins onto carriers |
US4123519A (en) * | 1976-08-17 | 1978-10-31 | Philips Roxane, Inc. | Injectable contraceptive vaccine and method |
US4140679A (en) * | 1976-10-12 | 1979-02-20 | Research Corporation | Antigen-protein complex for blocking allergic reactions |
US4192799A (en) * | 1977-09-21 | 1980-03-11 | The Upjohn Company | Conjugates formed by reacting a prostaglandin mimic compound with a carrier molecule |
US4223013A (en) * | 1978-12-29 | 1980-09-16 | Syva Company | Amitriptyline conjugates to antigenic proteins and enzymes |
US4238389A (en) * | 1979-02-12 | 1980-12-09 | Syva Company | Valproate conjugation using dicarbonyls |
Non-Patent Citations (1)
Title |
---|
See also references of EP0038357A4 * |
Cited By (448)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0237082A3 (en) * | 1986-03-14 | 1988-09-14 | Syntex (U.S.A.) Inc. | Transglutaminase inhibitors |
US4912120A (en) * | 1986-03-14 | 1990-03-27 | Syntex (U.S.A.) Inc. | 3,5-substituted 4,5-dihydroisoxazoles as transglutaminase inhibitors |
US4929630A (en) * | 1986-03-14 | 1990-05-29 | Syntex (U.S.A.) Inc. | Transglutaminase inhibitors |
AU599636B2 (en) * | 1986-03-14 | 1990-07-26 | Syntex (U.S.A.) Inc. | Transglutaminase inhibitors |
US4921941A (en) * | 1987-07-01 | 1990-05-01 | Schering Corporation | Orally active antiandrogens |
US5561119A (en) * | 1991-04-30 | 1996-10-01 | Laboratoires Hoechst | Glycosylated prodrugs, their method of preparation and their uses |
US7112317B2 (en) | 1992-03-05 | 2006-09-26 | Board Of Regents, The University Of Texas System | Combined methods and compositions for tumor vasculature targeting and tumor treatment |
US6093399A (en) * | 1992-03-05 | 2000-07-25 | Board Of Regents, The University Of Texas System | Methods and compositions for the specific coagulation of vasculature |
US6451312B1 (en) | 1992-03-05 | 2002-09-17 | Board Of Regents, The University Of Texas System | VEGF-gelonin for targeting the vasculature of solid tumors |
US7691380B2 (en) | 1992-03-05 | 2010-04-06 | Board Of Regents, The University Of Texas System | Combined methods for tumor coagulation and tumor treatment |
US6004554A (en) * | 1992-03-05 | 1999-12-21 | Board Of Regents, The University Of Texas System | Methods for targeting the vasculature of solid tumors |
US6749853B1 (en) | 1992-03-05 | 2004-06-15 | Board Of Regents, The University Of Texas System | Combined methods and compositions for coagulation and tumor treatment |
US5660827A (en) * | 1992-03-05 | 1997-08-26 | Board Of Regents, The University Of Texas System | Antibodies that bind to endoglin |
US7125541B2 (en) | 1992-03-05 | 2006-10-24 | The University Of Texas System Board Of Regents | Combined methods for tumor vasculature targeting and tumor treatment with radiotherapy |
US5855866A (en) * | 1992-03-05 | 1999-01-05 | Board Of Regenis, The University Of Texas System | Methods for treating the vasculature of solid tumors |
US5863538A (en) * | 1992-03-05 | 1999-01-26 | Board Of Regents, The University Of Texas System | Compositions for targeting the vasculature of solid tumors |
US5877289A (en) * | 1992-03-05 | 1999-03-02 | The Scripps Research Institute | Tissue factor compositions and ligands for the specific coagulation of vasculature |
US6051230A (en) * | 1992-03-05 | 2000-04-18 | Board Of Regents, The University Of Texas System | Compositions for targeting the vasculature of solid tumors |
US6036955A (en) * | 1992-03-05 | 2000-03-14 | The Scripps Research Institute | Kits and methods for the specific coagulation of vasculature |
US5965132A (en) * | 1992-03-05 | 1999-10-12 | Board Of Regents, The University Of Texas System | Methods and compositions for targeting the vasculature of solid tumors |
US6004555A (en) * | 1992-03-05 | 1999-12-21 | Board Of Regents, The University Of Texas System | Methods for the specific coagulation of vasculature |
US6146658A (en) * | 1992-10-27 | 2000-11-14 | Hoechst Aktiengesellschaft | Prodrugs, their preparation and use as pharmaceuticals |
US5955100A (en) * | 1992-10-27 | 1999-09-21 | Behringwerke Aktiengesellschaft | Prodrugs their preparation and use as pharmaceuticals |
DE4236237A1 (en) * | 1992-10-27 | 1994-04-28 | Behringwerke Ag | Prodrugs, their preparation and use as medicines |
EP0595133A3 (en) * | 1992-10-27 | 1998-11-04 | BEHRINGWERKE Aktiengesellschaft | Prodrugs, their preparation and use as medicaments |
US6214345B1 (en) | 1993-05-14 | 2001-04-10 | Bristol-Myers Squibb Co. | Lysosomal enzyme-cleavable antitumor drug conjugates |
EP0642799A1 (en) * | 1993-09-09 | 1995-03-15 | BEHRINGWERKE Aktiengesellschaft | Improved prodrugs for enzyme mediated activation |
US5621002A (en) * | 1993-09-09 | 1997-04-15 | Behringwerke Aktiengesellschaft | Prodrugs for enzyme mediated activation |
EP0647450A1 (en) * | 1993-09-09 | 1995-04-12 | BEHRINGWERKE Aktiengesellschaft | Improved prodrugs for enzyme mediated activation |
EP0648503A1 (en) * | 1993-09-22 | 1995-04-19 | BEHRINGWERKE Aktiengesellschaft | Pro-prodrugs, their production and use |
US5965566A (en) * | 1993-10-20 | 1999-10-12 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
US6127355A (en) * | 1993-10-20 | 2000-10-03 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
US5880131A (en) * | 1993-10-20 | 1999-03-09 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
WO1996001653A1 (en) * | 1994-07-11 | 1996-01-25 | Board Of Regents, The University Of Texas System | Methods and compositions for the specific coagulation of vasculature |
US7390629B2 (en) | 1994-08-19 | 2008-06-24 | La Region Wallonne | Tumor-activated prodrug compounds and treatment |
US7951772B2 (en) | 1994-08-19 | 2011-05-31 | La Region Wallonne | Tumor-activated prodrug compounds and treatment |
US7037898B2 (en) | 1994-08-19 | 2006-05-02 | Laregion Wallone | Tumor-activated prodrug compounds and treatment |
EP1619250A1 (en) | 1996-01-08 | 2006-01-25 | Genentech, Inc. | WSX receptor and ligands |
EP1650220A2 (en) | 1997-04-07 | 2006-04-26 | Genentech, Inc. | Anti-VEGF antibodies |
EP2336190A2 (en) | 1997-04-07 | 2011-06-22 | Genentech, Inc. | Anti-VEGF antibodies |
EP3260468A1 (en) | 1997-04-07 | 2017-12-27 | Genentech, Inc. | Anti-vegf antibodies |
EP2301580A1 (en) | 1997-04-07 | 2011-03-30 | Genentech, Inc. | Anti-VEGF antibodies |
EP2338915A2 (en) | 1997-04-07 | 2011-06-29 | Genentech, Inc. | Anti-VEGF antibodies |
US7052673B2 (en) | 1998-03-31 | 2006-05-30 | Bristol-Myers Squibb Pharma Company | Pharmaceuticals for the imaging of angiogenic disorders |
US6537520B1 (en) | 1998-03-31 | 2003-03-25 | Bristol-Myers Squibb Pharma Company | Pharmaceuticals for the imaging of angiogenic disorders |
US6548663B1 (en) | 1998-03-31 | 2003-04-15 | Bristol-Myers Squibb Pharma Company | Benzodiazepine vitronectin receptor antagonist pharmaceuticals |
US6524553B2 (en) | 1998-03-31 | 2003-02-25 | Bristol-Myers Squibb Pharma Company | Quinolone vitronectin receptor antagonist pharmaceuticals |
US6153655A (en) * | 1998-04-17 | 2000-11-28 | Enzon, Inc. | Terminally-branched polymeric linkers and polymeric conjugates containing the same |
US6395266B1 (en) | 1998-04-17 | 2002-05-28 | Enzon, Inc. | Terminally-branched polymeric linkers and polymeric conjugates containing the same |
US6638499B2 (en) | 1998-04-17 | 2003-10-28 | Enzon, Inc. | Terminally-branched polymeric linkers and polymeric conjugates containing the same |
EP3112468A1 (en) | 1998-05-15 | 2017-01-04 | Genentech, Inc. | Il-17 homologous polypeptides and therapeutic uses thereof |
EP2333069A2 (en) | 1998-05-15 | 2011-06-15 | Genentech, Inc. | Therapeutic uses of IL-17 homologous polypeptides |
EP2058334A2 (en) | 1998-06-12 | 2009-05-13 | Genentech, Inc. | Monoclonal antibodies, cross-reactive antibodies and method for producing the same |
EP1950300A2 (en) | 1998-11-18 | 2008-07-30 | Genentech, Inc. | Antibody variants with higher binding affinity compared to parent antibodies |
US6794518B1 (en) | 1998-12-18 | 2004-09-21 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
US7332149B1 (en) | 1998-12-18 | 2008-02-19 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
US6818201B2 (en) | 1998-12-18 | 2004-11-16 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
US7090828B2 (en) | 1998-12-18 | 2006-08-15 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
US6689337B2 (en) | 1998-12-18 | 2004-02-10 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
US6569402B1 (en) | 1998-12-18 | 2003-05-27 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
US6558649B1 (en) | 1998-12-18 | 2003-05-06 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
US6511649B1 (en) | 1998-12-18 | 2003-01-28 | Thomas D. Harris | Vitronectin receptor antagonist pharmaceuticals |
US7018611B2 (en) | 1998-12-18 | 2006-03-28 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
US6743412B2 (en) | 1998-12-18 | 2004-06-01 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
US7321045B2 (en) | 1998-12-18 | 2008-01-22 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
US6683163B2 (en) | 1998-12-18 | 2004-01-27 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
US6511648B2 (en) | 1998-12-18 | 2003-01-28 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
EP2112167A2 (en) | 1999-06-25 | 2009-10-28 | Genentech, Inc. | Humanized ANTI-ERBB2 antibodies and treatment with ANTI-ERBB2 antibodies |
EP2111870A1 (en) | 1999-08-27 | 2009-10-28 | Genentech, Inc. | Dosages for treatment of anti-erbB2 antibodies |
EP2110138A1 (en) | 1999-08-27 | 2009-10-21 | Genentech, Inc. | Dosages for treatment of anti-erbB2 antibodies |
US7741439B2 (en) | 2000-01-13 | 2010-06-22 | Genentech, Inc. | Isolated stra6 polypeptides |
US7855278B2 (en) | 2000-01-13 | 2010-12-21 | Genentech, Inc. | Antibodies to Stra6 polypeptides |
US7173115B2 (en) | 2000-01-13 | 2007-02-06 | Genentech, Inc. | Stra6 polypeptides |
US7939650B2 (en) | 2000-01-13 | 2011-05-10 | Genentech, Inc. | Stra6 polypeptides |
EP2857516A1 (en) | 2000-04-11 | 2015-04-08 | Genentech, Inc. | Multivalent antibodies and uses therefor |
US7696313B2 (en) | 2000-06-14 | 2010-04-13 | Medarex, Inc. | Prodrug compounds with isoleucine |
US7329507B2 (en) | 2000-06-14 | 2008-02-12 | Medarex, Inc. | Prodrug compounds with isoleucine |
US7115573B2 (en) | 2000-06-14 | 2006-10-03 | Medarex, Inc. | Prodrug compounds with an isoleucine |
EP2052742A1 (en) | 2000-06-20 | 2009-04-29 | Biogen Idec Inc. | Treatment of B-cell associated diseases such as malignancies and autoimmune diseases using a cold anti-CD20 antibody/radiolabeled anti-CD22 antibody combination |
EP2014303A2 (en) | 2000-07-27 | 2009-01-14 | Genentech, Inc. | APO-2L receptor agonist and CPT-11 synergism |
WO2002022833A1 (en) * | 2000-09-15 | 2002-03-21 | Universität Stuttgart | Fusion protein from antibody cytokine-cytokine inhibitor (selectokine) for use as target-specific prodrug |
WO2002030463A2 (en) | 2000-10-12 | 2002-04-18 | Genentech, Inc. | Reduced-viscosity concentrated protein formulations |
EP2065467A2 (en) | 2001-02-22 | 2009-06-03 | Genentech, Inc. | Anti-interferon-alpha antibodies |
EP2292301A2 (en) | 2001-02-22 | 2011-03-09 | Genentech, Inc. | Anti-interferon-alpha antibodies |
WO2002083180A1 (en) * | 2001-03-23 | 2002-10-24 | Syntarga B.V. | Elongated and multiple spacers in activatible prodrugs |
EP1243276A1 (en) * | 2001-03-23 | 2002-09-25 | Franciscus Marinus Hendrikus De Groot | Elongated and multiple spacers containing activatible prodrugs |
US7223837B2 (en) | 2001-03-23 | 2007-05-29 | Syntarga B.V. | Elongated and multiple spacers in activatible prodrugs |
EP2000545A1 (en) | 2001-06-20 | 2008-12-10 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
EP2000148A1 (en) | 2001-06-20 | 2008-12-10 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of prostate cancer |
EP2000482A1 (en) | 2001-06-20 | 2008-12-10 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
EP1992643A2 (en) | 2001-06-20 | 2008-11-19 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
EP2151244A1 (en) | 2001-09-18 | 2010-02-10 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
EP2143438A1 (en) | 2001-09-18 | 2010-01-13 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
EP2153843A1 (en) | 2001-09-18 | 2010-02-17 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
EP2067472A1 (en) | 2002-01-02 | 2009-06-10 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
US9745376B2 (en) | 2002-03-13 | 2017-08-29 | Biogen Ma Inc. | Anti-ανβ6 antibodies |
EP2011886A2 (en) | 2002-04-16 | 2009-01-07 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
EP2263691A1 (en) | 2002-07-15 | 2010-12-22 | Genentech, Inc. | Treatment of cancer with the recombinant humanized monoclonal anti-erbb2 antibody 2C4 (rhuMAb 2C4) |
EP2364996A1 (en) | 2002-09-27 | 2011-09-14 | Xencor Inc. | Optimized FC variants and methods for their generation |
EP3321282A1 (en) | 2002-09-27 | 2018-05-16 | Xencor, Inc. | Optimized fc variants and methods for their generation |
EP2345671A1 (en) | 2002-09-27 | 2011-07-20 | Xencor Inc. | Optimized fc variants and methods for their generation |
EP2042517A1 (en) | 2002-09-27 | 2009-04-01 | Xencor, Inc. | Optimized FC variants and methods for their generation |
EP2298805A2 (en) | 2002-09-27 | 2011-03-23 | Xencor, Inc. | Optimized Fc variants and methods for their generation |
EP3502133A1 (en) | 2002-09-27 | 2019-06-26 | Xencor, Inc. | Optimized fc variants and methods for their generation |
EP3150630A1 (en) | 2002-09-27 | 2017-04-05 | Xencor Inc. | Optimized fc variants and methods for their generation |
US8937158B2 (en) | 2003-03-03 | 2015-01-20 | Xencor, Inc. | Fc variants with increased affinity for FcγRIIc |
EP2335725A1 (en) | 2003-04-04 | 2011-06-22 | Genentech, Inc. | High concentration antibody and protein formulations |
EP3178492A1 (en) | 2003-04-04 | 2017-06-14 | Genentech, Inc. | High concentration antibody and protein formulations |
EP2062916A2 (en) | 2003-04-09 | 2009-05-27 | Genentech, Inc. | Therapy of autoimmune disease in a patient with an inadequate response to a TNF-Alpha inhibitor |
EP2368911A1 (en) | 2003-05-02 | 2011-09-28 | Xencor Inc. | Optimized Fc variants and methods for their generation |
EP3101030A1 (en) | 2003-05-02 | 2016-12-07 | Xencor, Inc. | Optimized fc variants and methods for their generation |
EP3838920A1 (en) | 2003-05-02 | 2021-06-23 | Xencor, Inc. | Optimized fc variants and methods for their generation |
EP2248829A1 (en) | 2003-05-30 | 2010-11-10 | Genentech, Inc. | Treatment with anti-VEGF antibodies |
EP2251355A1 (en) | 2003-05-30 | 2010-11-17 | Genentech, Inc. | Treatment with anti-VEGF antibodies |
EP2311875A1 (en) | 2003-05-30 | 2011-04-20 | Genentech, Inc. | Treatment with anti-VEGF antibodies |
US9714282B2 (en) | 2003-09-26 | 2017-07-25 | Xencor, Inc. | Optimized Fc variants and methods for their generation |
EP2295073A1 (en) | 2003-11-17 | 2011-03-16 | Genentech, Inc. | Antibody against CD22 for the treatment of tumour of hematopoietic origin |
EP2301568A1 (en) | 2003-11-17 | 2011-03-30 | Genentech, Inc. | Antibody against IRTA2 for the treatment of tumour of hematopoietic origin |
EP2161283A1 (en) | 2003-11-17 | 2010-03-10 | Genentech, Inc. | Compositions comprising antibodies against CD79b conjugated to a growth inhibitory agent or cytotoxic agent and methods for the treatment of tumor of hematopoietic origin |
EP3476861A1 (en) | 2004-01-07 | 2019-05-01 | Novartis Vaccines and Diagnostics, Inc. | M-csf-specific monoclonal antibody and uses thereof |
EP2311873A1 (en) | 2004-01-07 | 2011-04-20 | Novartis Vaccines and Diagnostics, Inc. | M-CSF-specific monoclonal antibody and uses thereof |
EP3653641A1 (en) | 2004-02-19 | 2020-05-20 | Genentech, Inc. | Cdr-repaired antibodies |
US9465029B2 (en) | 2004-04-16 | 2016-10-11 | Glaxo Group Limited | Methods for detecting LP-PLA2 activity and inhibition of LP-PLA2 activity |
US7655808B2 (en) | 2004-06-03 | 2010-02-02 | Bristol-Myers Squibb Company | Leptomycin compounds |
US7446196B2 (en) | 2004-06-03 | 2008-11-04 | Kosan Biosciences, Incorporated | Leptomycin compounds |
EP3130349A1 (en) | 2004-06-04 | 2017-02-15 | Genentech, Inc. | Method for treating multiple sclerosis |
US7541330B2 (en) | 2004-06-15 | 2009-06-02 | Kosan Biosciences Incorporated | Conjugates with reduced adverse systemic effects |
WO2006009901A2 (en) | 2004-06-18 | 2006-01-26 | Ambrx, Inc. | Novel antigen-binding polypeptides and their uses |
EP2471813A1 (en) | 2004-07-15 | 2012-07-04 | Xencor Inc. | Optimized Fc variants |
EP3342782A1 (en) | 2004-07-15 | 2018-07-04 | Xencor, Inc. | Optimized fc variants |
US10426736B2 (en) | 2004-08-26 | 2019-10-01 | Engeneic Molecular Delivery Pty. Ltd. | Delivering functional nucleic acids to mammalian cells via bacterially-derived, intact minicells |
US8669101B2 (en) | 2004-08-26 | 2014-03-11 | Engeneic Molecular Delivery Pty. Ltd. | Bacterially derived intact minicells that encompass plasmid free functional nucleic acid for in vivo delivery to mammalian cells |
US8691963B2 (en) | 2004-08-26 | 2014-04-08 | Engeneic Molecular Delivery Pty. Ltd. | Delivering functional nucleic acids to mammalian cells via bacterially-derived, intact minicells |
US9242007B2 (en) | 2004-08-26 | 2016-01-26 | Engeneic Molecular Delivery Pty. Ltd. | Delivering functional nucleic acids to mammalian cells via bacterially-derived, intact minicells |
US8956864B2 (en) | 2004-08-26 | 2015-02-17 | Engeneic Molecular Delivery Pty Ltd | Bacterially derived intact minicells that encompass plasmid free functional nucleic acid for in vivo delivery to mammalian cells |
US10441546B2 (en) | 2004-08-26 | 2019-10-15 | Engenelc Molecular Delivery Pty Ltd | Bacterially derived intact minicells that encompass plasmid free DNA and methods of using the same |
US10383827B2 (en) | 2004-08-26 | 2019-08-20 | Engeneic Molecular Delivery Pty Ltd | Bacterially-derived, intact minicells that encompass plasmid-free functional nucleic acid for in vivo delivery to mammalian cells |
US8735566B2 (en) | 2004-08-26 | 2014-05-27 | Engeneic Molecular Delivery Pty Ltd | Bacterially derived intact minicells that encompass plasmid free functional nucleic acid for in vivo delivery to mammalian cells |
US10098847B2 (en) | 2004-08-26 | 2018-10-16 | Engeneic Molecular Delivery Pty Ltd | Bacterially-derived, intact minicells that encompass plasmid-free functional nucleic acid for in vivo delivery to mammalian cells |
EP2386640A2 (en) | 2004-08-26 | 2011-11-16 | EnGeneIC Molecular Delivery Pty Ltd | Delivering functional nucleic acids to mammalian cells via bacterially-derived, intact minicells |
US9730897B2 (en) | 2004-08-26 | 2017-08-15 | Engeneic Molecular Delivery Pty Ltd | Delivering functional nucleic acids to mammalian cells via bacterially-derived, intact minicells |
US9066982B2 (en) | 2004-08-26 | 2015-06-30 | Engeneic Molecular Delivery Pty Ltd. | Bacterially-derived, intact minicells that encompass plasmid-free functional nucleic acid for in vivo delivery to mammalian cells |
US9200079B2 (en) | 2004-11-12 | 2015-12-01 | Xencor, Inc. | Fc variants with altered binding to FcRn |
US9803023B2 (en) | 2004-11-12 | 2017-10-31 | Xencor, Inc. | Fc variants with altered binding to FcRn |
US10336818B2 (en) | 2004-11-12 | 2019-07-02 | Xencor, Inc. | Fc variants with altered binding to FcRn |
US8852586B2 (en) | 2004-11-12 | 2014-10-07 | Xencor, Inc. | Fc variants with altered binding to FcRn |
US11198739B2 (en) | 2004-11-12 | 2021-12-14 | Xencor, Inc. | Fc variants with altered binding to FcRn |
US8883973B2 (en) | 2004-11-12 | 2014-11-11 | Xencor, Inc. | Fc variants with altered binding to FcRn |
EP2230517A1 (en) | 2005-01-07 | 2010-09-22 | Diadexus, Inc. | OVR110 antibody compositions and methods of use |
WO2006074418A2 (en) | 2005-01-07 | 2006-07-13 | Diadexus, Inc. | Ovr110 antibody compositions and methods of use |
US8409570B2 (en) | 2005-02-02 | 2013-04-02 | Genentech, Inc. | Method of inducing apoptosis using anti-DR5 antibodies |
US8030023B2 (en) | 2005-02-02 | 2011-10-04 | Genentech, Inc. | Nucleic acid encoding DR5 antibodies and uses thereof |
US8029783B2 (en) | 2005-02-02 | 2011-10-04 | Genentech, Inc. | DR5 antibodies and articles of manufacture containing same |
EP2548575A1 (en) | 2005-02-15 | 2013-01-23 | Duke University | Anti-CD19 antibodies that mediate ADCC for use in treating autoimmune diseases |
WO2006089133A2 (en) | 2005-02-15 | 2006-08-24 | Duke University | Anti-cd19 antibodies and uses in oncology |
EP2062591A1 (en) | 2005-04-07 | 2009-05-27 | Novartis Vaccines and Diagnostics, Inc. | CACNA1E in cancer diagnosis detection and treatment |
EP2083088A2 (en) | 2005-04-07 | 2009-07-29 | Novartis Vaccines and Diagnostics, Inc. | Cancer-related genes |
EP2221316A1 (en) | 2005-05-05 | 2010-08-25 | Duke University | Anti-CD19 antibody therapy for autoimmune disease |
US8992924B2 (en) | 2005-07-08 | 2015-03-31 | Biogen Idec Ma Inc. | Anti-ανβ6 antibodies and uses thereof |
EP2458013A1 (en) | 2005-07-08 | 2012-05-30 | Biogen Idec MA Inc. | Anti alpha v beta 6 antibodies and uses therof |
EP2458012A1 (en) | 2005-07-08 | 2012-05-30 | Biogen Idec MA Inc. | Anti alpha v beta 6 antibodies and uses thereof |
EP2447372A2 (en) | 2005-07-08 | 2012-05-02 | Biogen Idec MA Inc. | Anti alpha v beta 6 antibodies and uses thereof |
US8652469B2 (en) | 2005-07-28 | 2014-02-18 | Novartis Ag | M-CSF-specific monoclonal antibody and uses thereof |
US9040041B2 (en) | 2005-10-03 | 2015-05-26 | Xencor, Inc. | Modified FC molecules |
EP3023497A1 (en) | 2005-11-18 | 2016-05-25 | Glenmark Pharmaceuticals S.A. | Anti-alpha2 integrin antibodies and their uses |
EP2540741A1 (en) | 2006-03-06 | 2013-01-02 | Aeres Biomedical Limited | Humanized anti-CD22 antibodies and their use in treatment of oncology, transplantation and autoimmune disease |
US8278421B2 (en) | 2006-03-20 | 2012-10-02 | Xoma Techolology Ltd. | Human antibodies specific for gastrin materials and methods |
EP2389950A1 (en) | 2006-03-23 | 2011-11-30 | Novartis AG | Anti-tumor cell antigen antibody therapeutics |
EP2389946A1 (en) | 2006-03-23 | 2011-11-30 | Novartis AG | Anti-tumor cell antigen antibody therapeutics |
EP2389951A1 (en) | 2006-03-23 | 2011-11-30 | Novartis AG | Anti-tumor cell antigen antibody therapeutics |
EP2389949A1 (en) | 2006-03-23 | 2011-11-30 | Novartis AG | Anti-tumor cell antigen antibody therapeutics |
EP2389947A1 (en) | 2006-03-23 | 2011-11-30 | Novartis AG | Anti-tumor cell antigen antibody therapeutics |
EP2389948A1 (en) | 2006-03-23 | 2011-11-30 | Novartis AG | Anti-tumor cell antigen antibody therapeutics |
EP2614839A2 (en) | 2006-04-05 | 2013-07-17 | Genentech, Inc. | Method for using BOC/CDO to modulate hedgehog signaling |
EP2407483A1 (en) | 2006-04-13 | 2012-01-18 | Novartis Vaccines and Diagnostics, Inc. | Methods of treating, diagnosing or detecting cancers |
US8591862B2 (en) | 2006-06-23 | 2013-11-26 | Engeneic Molecular Delivery Pty Ltd | Targeted delivery of drugs, therapeutic nucleic acids and functional nucleic acids to mammalian cells via intact killed bacterial cells |
US11357860B2 (en) | 2006-06-23 | 2022-06-14 | Engeneic Molecular Delivery Pty Ltd | Targeted delivery of drugs, therapeutic nucleic acids and functional nucleic acids to mammalian cells via intact killed bacterial cells |
US11147883B2 (en) | 2006-06-23 | 2021-10-19 | EnGenlC Molecular Delivery Pty Ltd | Targeted delivery of drugs, therapeutic nucleic acids and functional nucleic acids to mammalian cells via intact killed bacterial cells |
US9878043B2 (en) | 2006-06-23 | 2018-01-30 | Engeneic Molecular Delivery Pty Ltd | Targeted delivery of drugs, therapeutic nucleic acids and functional nucleic acids to mammalian cells via intact killed bacterial cells |
EP2712618A1 (en) | 2006-06-23 | 2014-04-02 | EnGeneIC Molecular Delivery Pty Ltd. | Targeted delivery of drugs, therapeutic nucleic acids and functional nucleic acids to mammalian cells via intact killed bacterial cells |
USRE44681E1 (en) | 2006-07-10 | 2013-12-31 | Biogen Idec Ma Inc. | Compositions and methods for inhibiting growth of SMAD4-deficient cancers |
WO2008011081A2 (en) | 2006-07-19 | 2008-01-24 | The Trustees Of The University Of Pennsylvania | Wsx-1/p28 as a target for anti-inflammatory responses |
US8586716B2 (en) | 2006-08-04 | 2013-11-19 | Novartis Ag | EPHB3-specific antibody and uses thereof |
US9006398B2 (en) | 2006-08-04 | 2015-04-14 | Novartis Ag | EPHB3-specific antibody and uses thereof |
EP2383297A1 (en) | 2006-08-14 | 2011-11-02 | Xencor Inc. | Optimized antibodies that target CD19 |
EP3018144A1 (en) | 2006-08-18 | 2016-05-11 | XOMA Technology Ltd. | Prlr-specific antibody and uses thereof |
EP3415532A1 (en) | 2006-08-18 | 2018-12-19 | XOMA Technology Ltd. | Prlr-specific antibody and uses thereof |
EP2423231A2 (en) | 2006-08-18 | 2012-02-29 | Novartis AG | PRLR-specific antibody and uses thereof |
US9005614B2 (en) | 2006-08-18 | 2015-04-14 | Novartis Ag | PRLR-specific antibody and uses thereof |
EP2423332A1 (en) | 2006-08-25 | 2012-02-29 | Oncotherapy Science, Inc. | Prognostic markers and therapeutic targets for lung cancer |
EP2423333A1 (en) | 2006-08-25 | 2012-02-29 | Oncotherapy Science, Inc. | Prognostic markers and therapeutic targets for lung cancer |
EP2962697A1 (en) | 2006-11-27 | 2016-01-06 | diaDexus, Inc. | Ovr110 antibody compositions and methods of use |
EP2474556A2 (en) | 2007-03-14 | 2012-07-11 | Novartis AG | APCDD1 inhibitors for treating, diagnosing or detecting cancer |
EP3564372A1 (en) | 2007-03-30 | 2019-11-06 | EnGeneIC Molecular Delivery Pty Ltd. | Bacterially derived, intact minicells encompassing regulatory rna |
EP3205724A1 (en) | 2007-03-30 | 2017-08-16 | EnGeneIC Molecular Delivery Pty Ltd. | Bacterially derived, intact minicells encompassing regulatory rna |
EP2865755A2 (en) | 2007-03-30 | 2015-04-29 | EnGeneIC Molecular Delivery Pty Ltd | Bacterially derived, intact minicells encompassing regulatory RNA |
EP2532746A2 (en) | 2007-03-30 | 2012-12-12 | EnGeneIC Molecular Delivery Pty Ltd. | Bacterially-derived, intact minicells that encompass plasmid-free functional nucleic acid for in vivo delivery to mammalian cells |
EP2703011A2 (en) | 2007-05-07 | 2014-03-05 | MedImmune, LLC | Anti-icos antibodies and their use in treatment of oncology, transplantation and autoimmune disease |
EP2737907A2 (en) | 2007-05-07 | 2014-06-04 | MedImmune, LLC | Anti-icos antibodies and their use in treatment of oncology, transplantation and autoimmune disease |
US11434295B2 (en) | 2007-05-30 | 2022-09-06 | Xencor, Inc. | Methods and compositions for inhibiting CD32B expressing cells |
US9079960B2 (en) | 2007-05-30 | 2015-07-14 | Xencor, Inc. | Methods and compositions for inhibiting CD32B expressing cells |
US9902773B2 (en) | 2007-05-30 | 2018-02-27 | Xencor, Inc. | Methods and compositions for inhibiting CD32b expressing cells |
US9394366B2 (en) | 2007-05-30 | 2016-07-19 | Xencor, Inc. | Methods and compositions for inhibiting CD32B expressing cells |
US9914778B2 (en) | 2007-05-30 | 2018-03-13 | Xencor, Inc. | Methods and compositions for inhibiting CD32B expressing cells |
US11447552B2 (en) | 2007-05-30 | 2022-09-20 | Xencor, Inc. | Methods and compositions for inhibiting CD32B expressing cells |
US8063187B2 (en) | 2007-05-30 | 2011-11-22 | Xencor, Inc. | Methods and compositions for inhibiting CD32B expressing cells |
US9260523B2 (en) | 2007-05-30 | 2016-02-16 | Xencor, Inc. | Methods and compositions for inhibiting CD32b expressing cells |
EP2708557A1 (en) | 2007-05-30 | 2014-03-19 | Xencor, Inc. | Method and compositions for inhibiting CD32B expressing cells |
EP2641618A2 (en) | 2007-07-16 | 2013-09-25 | Genentech, Inc. | Humanized anti-CD79B antibodies and immunoconjugates and methods of use |
EP2474557A2 (en) | 2007-07-16 | 2012-07-11 | Genentech, Inc. | Anti-CD79b antibodies and immunoconjugates and methods of use |
EP2502937A2 (en) | 2007-07-16 | 2012-09-26 | Genentech, Inc. | Anti-CD 79b Antibodies And Immunoconjugates And Methods Of Use |
US8865875B2 (en) | 2007-08-22 | 2014-10-21 | Medarex, L.L.C. | Site-specific attachment of drugs or other agents to engineered antibodies with C-terminal extensions |
WO2009028158A1 (en) | 2007-08-24 | 2009-03-05 | Oncotherapy Science, Inc. | Dkk1 oncogene as therapeutic target for cancer and a diagnosing marker |
US8399623B2 (en) | 2007-10-01 | 2013-03-19 | Bristol-Myers Squibb Company | Human antibodies that bind mesothelin, and uses thereof |
US8268970B2 (en) | 2007-10-01 | 2012-09-18 | Bristol-Myers Squibb Company | Human antibodies that bind mesothelin, and uses thereof |
US8383779B2 (en) | 2007-10-01 | 2013-02-26 | Bristol-Myers Squibb Company | Human antibodies that bind mesothelin, and uses thereof |
US8425904B2 (en) | 2007-10-01 | 2013-04-23 | Bristol-Myers Squibb Company | Human antibodies that bind mesothelin, and uses thereof |
US11932685B2 (en) | 2007-10-31 | 2024-03-19 | Xencor, Inc. | Fc variants with altered binding to FcRn |
US8114402B2 (en) | 2007-11-12 | 2012-02-14 | Theraclone Sciences, Inc. | Compositions and methods for the therapy and diagnosis of influenza |
US8460671B2 (en) | 2007-11-12 | 2013-06-11 | Theraclone Sciences, Inc. | Compositions and methods for the therapy and diagnosis of influenza |
US8057796B2 (en) | 2007-11-12 | 2011-11-15 | Theraclone Sciences, Inc. | Compositions and methods for the therapy and diagnosis of influenza |
US8236315B2 (en) | 2008-01-23 | 2012-08-07 | Glenmark Pharmaceuticals, S.A. | Humanized antibodies specific for von Willebrand factor |
EP2657253A2 (en) | 2008-01-31 | 2013-10-30 | Genentech, Inc. | Anti-CD79b antibodies and immunoconjugates and methods of use |
US8852594B2 (en) | 2008-03-10 | 2014-10-07 | Theraclone Sciences, Inc. | Compositions and methods for the therapy and diagnosis of cytomegalovirus infections |
US7982012B2 (en) | 2008-03-10 | 2011-07-19 | Theraclone Sciences, Inc. | Compositions and methods for the therapy and diagnosis of cytomegalovirus |
US8268309B2 (en) | 2008-03-10 | 2012-09-18 | Theraclone Sciences, Inc. | Compositions and methods for the therapy and diagnosis of cytomegalovirus |
WO2010001585A1 (en) | 2008-06-30 | 2010-01-07 | Oncotherapy Science, Inc. | Anti-cdh3 antibodies labeled with radioisotope label and uses thereof |
EP3095463A2 (en) | 2008-09-16 | 2016-11-23 | F. Hoffmann-La Roche AG | Methods for treating progressive multiple sclerosis |
US9994642B2 (en) | 2008-09-16 | 2018-06-12 | Genentech, Inc. | Methods for treating progressive multiple sclerosis |
US9683047B2 (en) | 2008-09-16 | 2017-06-20 | Genentech, Inc. | Methods for treating progressive multiple sclerosis |
EP3747464A1 (en) | 2008-09-16 | 2020-12-09 | F. Hoffmann-La Roche AG | Methods for treating progessive multiple sclerosis using an anti-cd20 antibody |
US8298531B2 (en) | 2008-11-06 | 2012-10-30 | Glenmark Pharmaceuticals, S.A. | Treatment with anti-alpha2 integrin antibodies |
WO2010056804A1 (en) | 2008-11-12 | 2010-05-20 | Medimmune, Llc | Antibody formulation |
WO2010060920A1 (en) | 2008-11-27 | 2010-06-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Cxcl4l1 as a biomarker of pancreatic cancer |
EP4209510A1 (en) | 2008-12-09 | 2023-07-12 | F. Hoffmann-La Roche AG | Anti-pd-l1 antibodies and their use to enhance t-cell function |
EP3255060A1 (en) | 2008-12-09 | 2017-12-13 | F. Hoffmann-La Roche AG | Anti-pd-l1 antibodies and their use to enhance t-cell function |
EP4331604A2 (en) | 2008-12-09 | 2024-03-06 | F. Hoffmann-La Roche AG | Anti-pd-l1 antibodies and their use to enhance t-cell function |
EP3447073A1 (en) | 2008-12-09 | 2019-02-27 | F. Hoffmann-La Roche AG | Anti-pd-l1 antibodies and their use to enhance t-cell function |
EP3929216A1 (en) | 2008-12-09 | 2021-12-29 | F. Hoffmann-La Roche AG | Anti-pd-l1 antibodies and their use to enhance t-cell function |
EP4169951A1 (en) | 2008-12-09 | 2023-04-26 | F. Hoffmann-La Roche AG | Anti-pd-l1 antibodies and their use to enhance t-cell function |
WO2010077634A1 (en) | 2008-12-09 | 2010-07-08 | Genentech, Inc. | Anti-pd-l1 antibodies and their use to enhance t-cell function |
WO2010102175A1 (en) | 2009-03-05 | 2010-09-10 | Medarex, Inc. | Fully human antibodies specific to cadm1 |
EP3260136A1 (en) | 2009-03-17 | 2017-12-27 | Theraclone Sciences, Inc. | Human immunodeficiency virus (hiv) -neutralizing antibodies |
EP4085925A1 (en) | 2009-03-17 | 2022-11-09 | International AIDS Vaccine Initiative | Human immunodeficiency virus (hiv)-neutralizing antibodies |
EP3323427A1 (en) | 2009-03-17 | 2018-05-23 | Theraclone Sciences, Inc. | Human immunodeficiency virus (hiv)-neutralizing antibodies |
WO2010120561A1 (en) | 2009-04-01 | 2010-10-21 | Genentech, Inc. | Anti-fcrh5 antibodies and immunoconjugates and methods of use |
US8609101B2 (en) | 2009-04-23 | 2013-12-17 | Theraclone Sciences, Inc. | Granulocyte-macrophage colony-stimulating factor (GM-CSF) neutralizing antibodies |
US8858948B2 (en) | 2009-05-20 | 2014-10-14 | Theraclone Sciences, Inc. | Compositions and methods for the therapy and diagnosis of influenza |
WO2011017249A1 (en) | 2009-08-03 | 2011-02-10 | Medarex, Inc. | Antiproliferative compounds, conjugates thereof, methods therefor, and uses thereof |
US10662237B2 (en) | 2009-08-06 | 2020-05-26 | Genentech, Inc. | Method to improve virus filtration capacity |
WO2011031397A1 (en) | 2009-08-06 | 2011-03-17 | Genentech, Inc. | Method to improve virus removal in protein purification |
US11225513B2 (en) | 2009-08-06 | 2022-01-18 | Genentech, Inc. | Method to improve virus filtration capacity |
EP3309168A1 (en) | 2009-08-06 | 2018-04-18 | F. Hoffmann-La Roche AG | Method to improve virus removal in protein purification |
US11401348B2 (en) | 2009-09-02 | 2022-08-02 | Xencor, Inc. | Heterodimeric Fc variants |
WO2011038302A2 (en) | 2009-09-25 | 2011-03-31 | Xoma Technology Ltd. | Novel modulators |
EP2957296A1 (en) | 2009-09-25 | 2015-12-23 | Xoma (Us) Llc | Insulin receptor binding antibodies |
EP3187877A1 (en) | 2009-09-25 | 2017-07-05 | XOMA Technology Ltd. | Screening methods |
WO2011038301A2 (en) | 2009-09-25 | 2011-03-31 | Xoma Technology Ltd. | Screening methods |
WO2011050194A1 (en) | 2009-10-22 | 2011-04-28 | Genentech, Inc. | Methods and compositions for modulating hepsin activation of macrophage-stimulating protein |
US8697386B2 (en) | 2009-10-22 | 2014-04-15 | Genentech, Inc. | Methods and compositions for modulating hepsin activation of macrophage-stimulating protein |
US9260517B2 (en) | 2009-11-17 | 2016-02-16 | Musc Foundation For Research Development | Human monoclonal antibodies to human nucleolin |
US10385128B2 (en) | 2009-11-17 | 2019-08-20 | Musc Foundation For Research Development | Nucleolin antibodies |
EP3037435A1 (en) | 2009-11-17 | 2016-06-29 | MUSC Foundation For Research Development | Human monoclonal antibodies to human nucleolin |
WO2011066503A2 (en) | 2009-11-30 | 2011-06-03 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
EP3002297A2 (en) | 2009-11-30 | 2016-04-06 | F. Hoffmann-La Roche AG | Antibodies for treating and diagnosing tumors expressing slc34a2 (tat211) |
WO2011076922A1 (en) | 2009-12-23 | 2011-06-30 | Synimmune Gmbh | Anti-flt3 antibodies and methods of using the same |
EP3450459A2 (en) | 2009-12-28 | 2019-03-06 | OncoTherapy Science, Inc. | Anti-cdh3 antibodies and uses thereof |
WO2011089211A1 (en) | 2010-01-22 | 2011-07-28 | Synimmune Gmbh | Anti-cd133 antibodies and methods of using the same |
EP3590966A1 (en) | 2010-02-23 | 2020-01-08 | Sanofi | Anti-alpha2 integrin antibodies and their uses |
WO2011104604A2 (en) | 2010-02-23 | 2011-09-01 | Glenmark Pharmaceuticals S.A. | Anti-alpha2 integrin antibodies and their uses |
WO2011106297A2 (en) | 2010-02-23 | 2011-09-01 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
EP2848632A1 (en) | 2010-02-23 | 2015-03-18 | Sanofi | Anti-alpha2 integrin antibodies and their uses |
EP3208281A1 (en) | 2010-03-29 | 2017-08-23 | Zymeworks, Inc. | Antibodies with enhanced or suppressed effector function |
EP3178851A1 (en) | 2010-03-31 | 2017-06-14 | Boehringer Ingelheim International GmbH | Anti-cd40 antibodies |
EP2796467A1 (en) | 2010-03-31 | 2014-10-29 | Boehringer Ingelheim International GmbH | Anti-CD40 antibodies |
WO2011139985A1 (en) | 2010-05-03 | 2011-11-10 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
US9000135B2 (en) | 2010-05-20 | 2015-04-07 | Centre Nationale De Recherche Scientifique | Self-reactive arms and prodrugs comprising same |
WO2011145068A1 (en) | 2010-05-20 | 2011-11-24 | Centre National De La Recherche Scientifique | Novel self-reactive arms and prodrugs comprising same |
US8900590B2 (en) | 2010-08-12 | 2014-12-02 | Theraclone Sciences, Inc. | Anti-hemagglutinin antibody compositions and methods of use thereof |
EP4085924A1 (en) | 2010-08-31 | 2022-11-09 | Theraclone Sciences, Inc. | Human immunodeficiency virus (hiv)-neutralizing antibodies |
EP3556396A1 (en) | 2010-08-31 | 2019-10-23 | Theraclone Science, Int. | Human immunodeficiency virus (hiv)-neutralizing antibodies |
EP2926830A2 (en) | 2010-08-31 | 2015-10-07 | Theraclone Sciences, Inc. | Human immunodeficiency virus (HIV)-neutralizing antibodies |
EP4226935A2 (en) | 2010-08-31 | 2023-08-16 | Theraclone Sciences, Inc. | Human immunodeficiency virus (hiv)-neutralizing antibodies |
US9085621B2 (en) | 2010-09-10 | 2015-07-21 | Apexigen, Inc. | Anti-IL-1β antibodies |
EP3115375A1 (en) | 2010-11-04 | 2017-01-11 | Boehringer Ingelheim International GmbH | Anti-il-23 antibodies |
EP3281954A1 (en) | 2010-11-04 | 2018-02-14 | Boehringer Ingelheim International GmbH | Anti-il-23 antibodies |
WO2012061448A1 (en) | 2010-11-04 | 2012-05-10 | Boehringer Ingelheim International Gmbh | Anti-il-23 antibodies |
EP3456740A1 (en) | 2010-11-04 | 2019-03-20 | Boehringer Ingelheim International GmbH | Anti-il-23 antibodies |
WO2012085111A1 (en) | 2010-12-23 | 2012-06-28 | F. Hoffmann-La Roche Ag | Polypeptide-polynucleotide-complex and its use in targeted effector moiety delivery |
WO2012109624A2 (en) | 2011-02-11 | 2012-08-16 | Zyngenia, Inc. | Monovalent and multivalent multispecific complexes and uses thereof |
US8916160B2 (en) | 2011-02-14 | 2014-12-23 | Theraclone Sciences, Inc. | Compositions and methods for the therapy and diagnosis of influenza |
WO2012118813A2 (en) | 2011-03-03 | 2012-09-07 | Apexigen, Inc. | Anti-il-6 receptor antibodies and methods of use |
WO2012122513A2 (en) | 2011-03-10 | 2012-09-13 | Omeros Corporation | Generation of anti-fn14 monoclonal antibodies by ex-vivo accelerated antibody evolution |
WO2012125614A1 (en) | 2011-03-15 | 2012-09-20 | Theraclone Sciences, Inc. | Compositions and methods for the therapy and diagnosis of influenza |
WO2012149356A2 (en) | 2011-04-29 | 2012-11-01 | Apexigen, Inc. | Anti-cd40 antibodies and methods of use |
EP3508500A1 (en) | 2011-04-29 | 2019-07-10 | Apexigen, Inc. | Anti-cd40 antibodies and methods of use |
WO2012162561A2 (en) | 2011-05-24 | 2012-11-29 | Zyngenia, Inc. | Multivalent and monovalent multispecific complexes and their uses |
WO2012167143A1 (en) | 2011-06-03 | 2012-12-06 | Xoma Technology Ltd. | Antibodies specific for tgf-beta |
EP3954704A1 (en) | 2011-06-03 | 2022-02-16 | XOMA Technology Ltd. | Antibodies specific for tgf-beta |
EP3392274A1 (en) | 2011-08-12 | 2018-10-24 | Omeros Corporation | Anti-fzd10 monoclonal antibodies and methods for their use |
EP3783028A1 (en) | 2011-08-12 | 2021-02-24 | Omeros Corporation | Anti-fzd10 monoclonal antibodies and methods for their use |
WO2013033069A1 (en) | 2011-08-30 | 2013-03-07 | Theraclone Sciences, Inc. | Human rhinovirus (hrv) antibodies |
US8822651B2 (en) | 2011-08-30 | 2014-09-02 | Theraclone Sciences, Inc. | Human rhinovirus (HRV) antibodies |
WO2013063001A1 (en) | 2011-10-28 | 2013-05-02 | Genentech, Inc. | Therapeutic combinations and methods of treating melanoma |
WO2013067098A1 (en) | 2011-11-02 | 2013-05-10 | Apexigen, Inc. | Anti-kdr antibodies and methods of use |
EP3536710A1 (en) | 2011-11-16 | 2019-09-11 | Boehringer Ingelheim International GmbH | Anti il-36r antibodies |
WO2013074569A1 (en) | 2011-11-16 | 2013-05-23 | Boehringer Ingelheim International Gmbh | Anti il-36r antibodies |
WO2013101771A2 (en) | 2011-12-30 | 2013-07-04 | Genentech, Inc. | Compositions and method for treating autoimmune diseases |
WO2013116287A1 (en) | 2012-01-31 | 2013-08-08 | Genentech, Inc. | Anti-ig-e m1' antibodies and methods using same |
US8709431B2 (en) | 2012-02-13 | 2014-04-29 | Bristol-Myers Squibb Company | Enediyne compounds, conjugates thereof, and uses and methods therefor |
US9156850B2 (en) | 2012-02-13 | 2015-10-13 | Bristol-Myers Squibb Company | Enediyne compounds, conjugates thereof, and uses and methods therefor |
WO2013122823A1 (en) | 2012-02-13 | 2013-08-22 | Bristol-Myers Squibb Company | Enediyne compounds, conjugates thereof, and uses and methods therefor |
WO2013149159A1 (en) | 2012-03-30 | 2013-10-03 | Genentech, Inc. | Anti-lgr5 antibodies and immunoconjugates |
US9175089B2 (en) | 2012-03-30 | 2015-11-03 | Genentech, Inc. | Anti-LGR5 antibodies and immunoconjugates |
US9597411B2 (en) | 2012-05-01 | 2017-03-21 | Genentech, Inc. | Anti-PMEL17 antibodies and immunoconjugates |
US9056910B2 (en) | 2012-05-01 | 2015-06-16 | Genentech, Inc. | Anti-PMEL17 antibodies and immunoconjugates |
US10196454B2 (en) | 2012-05-01 | 2019-02-05 | Genentech, Inc. | Anti-PMEL17 antibodies and immunoconjugates |
WO2013165940A1 (en) | 2012-05-01 | 2013-11-07 | Genentech, Inc. | Anti-pmel17 antibodies and immunoconjugates |
EP4039275A1 (en) | 2012-05-03 | 2022-08-10 | Boehringer Ingelheim International GmbH | Anti-il-23p19 antibodies |
EP3326649A1 (en) | 2012-05-03 | 2018-05-30 | Boehringer Ingelheim International GmbH | Anti-il-23p19 antibodies |
WO2013165791A1 (en) | 2012-05-03 | 2013-11-07 | Boehringer Ingelheim International Gmbh | Anti-il-23p19 antibodies |
WO2013185114A2 (en) | 2012-06-08 | 2013-12-12 | Biogen Idec Ma Inc. | Chimeric clotting factors |
EP4079316A1 (en) | 2012-06-08 | 2022-10-26 | Bioverativ Therapeutics Inc. | Procoagulant compounds |
US11261437B2 (en) | 2012-06-08 | 2022-03-01 | Bioverativ Therapeutics Inc. | Procoagulant compounds |
US11168316B2 (en) | 2012-06-08 | 2021-11-09 | Bioverativ Therapeutics, Inc. | Chimeric clotting factors |
EP3693000A1 (en) | 2012-06-08 | 2020-08-12 | Bioverativ Therapeutics Inc. | Procoagulant compounds |
US10202595B2 (en) | 2012-06-08 | 2019-02-12 | Bioverativ Therapeutics Inc. | Chimeric clotting factors |
US10287564B2 (en) | 2012-06-08 | 2019-05-14 | Bioverativ Therapeutics Inc. | Procoagulant compounds |
US9278131B2 (en) | 2012-08-10 | 2016-03-08 | Adocia | Process for lowering the viscosity of highly concentrated protein solutions |
WO2014027959A1 (en) | 2012-08-14 | 2014-02-20 | Nanyang Technological University | Angiopoietin-like 4 antibody and a method of its use in cancer treatment |
WO2014047199A1 (en) * | 2012-09-19 | 2014-03-27 | The Research Foundation For The State University Of New York | Novel prodrugs for selective anticancer therapy |
US9872919B2 (en) | 2012-09-19 | 2018-01-23 | The Research Foundation For The State University Of New York | Prodrugs for selective anticancer therapy |
EP3925977A1 (en) | 2012-10-30 | 2021-12-22 | Apexigen, Inc. | Anti-cd40 antibodies and methods of use |
US9617345B2 (en) | 2012-11-20 | 2017-04-11 | Sanofi | Anti-CEACAM5 antibodies and uses thereof |
US10457739B2 (en) | 2012-11-20 | 2019-10-29 | Sanofi | Anti-CEACAM5 antibodies and uses thereof |
WO2014079886A1 (en) | 2012-11-20 | 2014-05-30 | Sanofi | Anti-ceacam5 antibodies and uses thereof |
EP3594243A1 (en) | 2012-11-20 | 2020-01-15 | Sanofi | Anti-ceacam5 antibodies and uses thereof |
US11332542B2 (en) | 2012-11-20 | 2022-05-17 | Sanofi | Anti-CEACAM5 antibodies and uses thereof |
US9809653B2 (en) | 2012-12-27 | 2017-11-07 | Sanofi | Anti-LAMP1 antibodies and antibody drug conjugates, and uses thereof |
WO2014126836A1 (en) | 2013-02-14 | 2014-08-21 | Bristol-Myers Squibb Company | Tubulysin compounds, methods of making and use |
US9382289B2 (en) | 2013-02-14 | 2016-07-05 | Bristol-Myers Squibb Company | Tubulysin compounds, methods of making and use |
US9109008B2 (en) | 2013-02-14 | 2015-08-18 | Bristol-Myers Squibb Company | Tubulysin compounds, methods of making and use |
US9688721B2 (en) | 2013-02-14 | 2017-06-27 | Bristol-Myers Squibb Company | Tubulysin compounds, methods of making and use |
US8980824B2 (en) | 2013-02-14 | 2015-03-17 | Bristol-Myers Squibb Company | Tubulysin compounds, methods of making and use |
WO2014159835A1 (en) | 2013-03-14 | 2014-10-02 | Genentech, Inc. | Anti-b7-h4 antibodies and immunoconjugates |
US10150813B2 (en) | 2013-03-14 | 2018-12-11 | Genentech, Inc. | Anti-B7-H4 antibodies and immunoconjugates |
US9562099B2 (en) | 2013-03-14 | 2017-02-07 | Genentech, Inc. | Anti-B7-H4 antibodies and immunoconjugates |
EP3299391A1 (en) | 2013-03-14 | 2018-03-28 | Genentech, Inc. | Anti-b7-h4 antibodies and immunoconjugates |
US11230600B2 (en) | 2013-03-14 | 2022-01-25 | Genentech, Inc. | Anti-B7-H4 antibodies and immunoconjugates |
US9000132B2 (en) | 2013-03-15 | 2015-04-07 | Diadexus, Inc. | Lipoprotein-associated phospholipase A2 antibody compositions and methods of use |
US10035859B2 (en) | 2013-03-15 | 2018-07-31 | Biogen Ma Inc. | Anti-alpha V beta 6 antibodies and uses thereof |
US10035860B2 (en) | 2013-03-15 | 2018-07-31 | Biogen Ma Inc. | Anti-alpha V beta 6 antibodies and uses thereof |
WO2015023596A1 (en) | 2013-08-12 | 2015-02-19 | Genentech, Inc. | Compositions and method for treating complement-associated conditions |
US10246515B2 (en) | 2013-09-17 | 2019-04-02 | Genentech, Inc. | Methods of treating hedgehog-related diseases with an anti-LGR5 antibody |
WO2015042108A1 (en) | 2013-09-17 | 2015-03-26 | Genentech, Inc. | Methods of using anti-lgr5 antibodies |
WO2015089344A1 (en) | 2013-12-13 | 2015-06-18 | Genentech, Inc. | Anti-cd33 antibodies and immunoconjugates |
EP3461845A1 (en) | 2013-12-13 | 2019-04-03 | Genentech, Inc. | Anti-cd33 antibodies and immunoconjugates |
WO2015095227A2 (en) | 2013-12-16 | 2015-06-25 | Genentech, Inc. | Peptidomimetic compounds and antibody-drug conjugates thereof |
WO2015112909A1 (en) | 2014-01-24 | 2015-07-30 | Genentech, Inc. | Methods of using anti-steap1 antibodies and immunoconjugates |
WO2016039801A1 (en) | 2014-01-31 | 2016-03-17 | Boehringer Ingelheim International Gmbh | Novel anti-baff antibodies |
WO2015179658A2 (en) | 2014-05-22 | 2015-11-26 | Genentech, Inc. | Anti-gpc3 antibodies and immunoconjugates |
US11584927B2 (en) | 2014-08-28 | 2023-02-21 | Bioatla, Inc. | Conditionally active chimeric antigen receptors for modified T-cells |
US11286302B2 (en) | 2014-09-12 | 2022-03-29 | Genentech, Inc. | Anti-B7-H4 antibodies and immunoconjugates |
US10059768B2 (en) | 2014-09-12 | 2018-08-28 | Genentech, Inc. | Anti-B7-H4 antibodies and immunoconjugates |
EP3782654A1 (en) | 2014-09-12 | 2021-02-24 | Genentech, Inc. | Anti-her2 antibodies and immunoconjugates |
WO2016040868A1 (en) | 2014-09-12 | 2016-03-17 | Genentech, Inc. | Anti-cll-1 antibodies and immunoconjugates |
EP3693391A1 (en) | 2014-09-12 | 2020-08-12 | Genentech, Inc. | Anti-cll-1 antibodies and immunoconjugates |
EP3689910A2 (en) | 2014-09-23 | 2020-08-05 | F. Hoffmann-La Roche AG | Method of using anti-cd79b immunoconjugates |
WO2016077260A1 (en) | 2014-11-10 | 2016-05-19 | Bristol-Myers Squibb Company | Tubulysin analogs and methods of making and use |
WO2016115201A1 (en) | 2015-01-14 | 2016-07-21 | Bristol-Myers Squibb Company | Heteroarylene-bridged benzodiazepine dimers, conjugates thereof, and methods of making and using |
WO2016141111A1 (en) | 2015-03-03 | 2016-09-09 | Xoma (Us) Llc | Treatment of post-prandial hyperinsulinemia and hypoglycemia after bariatric surgery |
US10711067B2 (en) | 2015-03-03 | 2020-07-14 | Xoma (Us) Llc | Treatment of post-prandial hyperinsulinemia and hypoglycemia after bariatric surgery |
US10683347B2 (en) | 2015-04-03 | 2020-06-16 | Xoma Technology Ltd. | Treatment of cancer using anti-TGF-β and anti-PD-1 antibodies |
US11685775B2 (en) | 2015-04-03 | 2023-06-27 | Xoma Technology Ltd. | Method of increasing the ratio of effector T cells to regulatory T cells in a tumor by administering to a subject a TGF-beta inhibitor and a PD-1 antibody |
WO2016161410A2 (en) | 2015-04-03 | 2016-10-06 | Xoma Technology Ltd. | Treatment of cancer using inhibitors of tgf-beta and pd-1 |
EP3770171A1 (en) | 2015-04-03 | 2021-01-27 | XOMA Technology Ltd. | Treatment of cancer using inhibitors of tgf-beta and pd-1 |
US10167334B2 (en) | 2015-04-03 | 2019-01-01 | Xoma Technology Ltd. | Treatment of cancer using anti-TGF-BETA and PD-1 antibodies |
US11254987B2 (en) | 2015-05-29 | 2022-02-22 | Genentech, Inc. | PD-L1 promoter methylation in cancer |
EP3763827A1 (en) | 2015-05-29 | 2021-01-13 | F. Hoffmann-La Roche AG | Pd-l1 promoter methylation in cancer |
WO2016196381A1 (en) | 2015-05-29 | 2016-12-08 | Genentech, Inc. | Pd-l1 promoter methylation in cancer |
US10253101B2 (en) | 2015-08-06 | 2019-04-09 | Xoma (Us) Llc | Antibody fragments against the insulin receptor and uses thereof to treat hypoglycemia |
WO2017062682A2 (en) | 2015-10-06 | 2017-04-13 | Genentech, Inc. | Method for treating multiple sclerosis |
US11357849B2 (en) | 2016-03-07 | 2022-06-14 | Musc Foundation For Research Development | Anti-nucleolin antibodies |
US11897959B2 (en) | 2016-04-15 | 2024-02-13 | Bioatla, Inc. | Anti-AXL antibodies, antibody fragments and their immunoconjugates and uses thereof |
US11149088B2 (en) | 2016-04-15 | 2021-10-19 | Bioatla, Inc. | Anti-Axl antibodies, antibody fragments and their immunoconjugates and uses thereof |
WO2017194568A1 (en) | 2016-05-11 | 2017-11-16 | Sanofi | Treatment regimen using anti-muc1 maytansinoid immunoconjugate antibody for the treatment of tumors |
EP4122958A1 (en) | 2016-05-13 | 2023-01-25 | BioAtla, Inc. | Anti-ror2 antibodies, antibody fragments, their immunoconjugates and uses thereof |
US11879011B2 (en) | 2016-05-13 | 2024-01-23 | Bioatla, Inc. | Anti-ROR2 antibodies, antibody fragments, their immunoconjucates and uses thereof |
US11254742B2 (en) | 2016-05-13 | 2022-02-22 | Bioatla, Inc. | Anti-Ror2 antibodies, antibody fragments, their immunoconjugates and uses thereof |
WO2017197234A1 (en) | 2016-05-13 | 2017-11-16 | Bioatla, Llc | Anti-ror2 antibodies, antibody fragments, their immunoconjugates and uses thereof |
US11365256B2 (en) | 2016-06-08 | 2022-06-21 | Xencor, Inc. | Methods and compositions for inhibiting CD32B expressing cells in IGG4-related diseases |
WO2017214452A1 (en) | 2016-06-08 | 2017-12-14 | Xencor, Inc. | Treatment of igg4-related diseases with anti-cd19 antibodies crossbinding to cd32b |
WO2018026748A1 (en) | 2016-08-01 | 2018-02-08 | Xoma (Us) Llc | Parathyroid hormone receptor 1 (pth1r) antibodies and uses thereof |
US11787876B2 (en) | 2016-08-01 | 2023-10-17 | Xoma (Us) Llc | Parathyroid hormone receptor 1 (PTH1R) antibodies and uses thereof |
US10519250B2 (en) | 2016-08-01 | 2019-12-31 | Xoma (Us) Llc | Parathyroid hormone receptor 1 (PTH1R) antibodies and uses thereof |
WO2018035391A1 (en) | 2016-08-19 | 2018-02-22 | Bristol-Myers Squibb Company | Seco-cyclopropapyrroloindole compounds, antibody-drug conjugates thereof, and methods of making and use |
WO2018075842A1 (en) | 2016-10-20 | 2018-04-26 | Bristol-Myers Squibb Company | Condensed benzodiazepine derivatives and conjugates made therefrom |
WO2018091724A1 (en) | 2016-11-21 | 2018-05-24 | Cureab Gmbh | Anti-gp73 antibodies and immunoconjugates |
EP4015532A1 (en) | 2016-11-21 | 2022-06-22 | cureab GmbH | Anti-gp73 antibodies and immunoconjugates |
WO2018134412A1 (en) * | 2017-01-20 | 2018-07-26 | Biosynth Ag | Antimicrobial compounds and uses thereof |
US11185534B2 (en) * | 2017-02-01 | 2021-11-30 | The Johns Hopkins University | Prodrugs of glutamine analogs |
EP3576727A4 (en) * | 2017-02-01 | 2020-09-09 | The Johns Hopkins University | Prodrugs of glutamine analogs |
WO2018183173A1 (en) | 2017-03-27 | 2018-10-04 | Boehringer Ingelheim International Gmbh | Anti il-36r antibodies combination therapy |
WO2019035968A1 (en) | 2017-08-16 | 2019-02-21 | Bristol-Myers Squibb Company | 6-amino-7,9-dihydro-8h-purin-8-one derivatives as toll-like receptor 7 (tlr7) agonists as immunostimulants |
WO2019035971A1 (en) | 2017-08-16 | 2019-02-21 | Bristol-Myers Squibb Company | 6-amino-7,9-dihydro-8h-purin-8-one derivatives as immunostimulant toll-like receptor 7 (tlr7) agonists |
WO2019035969A1 (en) | 2017-08-16 | 2019-02-21 | Bristol-Myers Squibb Company | Toll-like receptor 7 (tlr7) agonists having a tricyclic moiety, conjugates thereof, and methods and uses therefor |
WO2019035970A1 (en) | 2017-08-16 | 2019-02-21 | Bristol-Myers Squibb Company | 6-amino-7,9-dihydro-8h-purin-8-one derivatives as immunostimulant toll-like receptor 7 (tlr7) agonists |
WO2019036023A1 (en) | 2017-08-16 | 2019-02-21 | Bristol-Myers Squibb Company | 6-amino-7,9-dihydro-8h-purin-8-one derivatives as immunostimulant toll-like receptor 7 (tlr7) agonists |
WO2019209811A1 (en) | 2018-04-24 | 2019-10-31 | Bristol-Myers Squibb Company | Macrocyclic toll-like receptor 7 (tlr7) agonists |
US11911483B2 (en) | 2018-05-29 | 2024-02-27 | Bristol-Myers Squibb Company | Modified self-immolating moieties for use in prodrugs and conjugates and methods of using and making |
WO2019231879A1 (en) | 2018-05-29 | 2019-12-05 | Bristol-Myers Squibb Company | Modified self-immolating moieties for use in prodrugs and conjugates and methods of using and making |
US10898578B2 (en) | 2018-05-29 | 2021-01-26 | Bristol-Myers Squibb Company | Modified self-immolating moieties for use in prodrugs and conjugates and methods of using and making |
WO2020006347A1 (en) | 2018-06-29 | 2020-01-02 | Boehringer Ingelheim International Gmbh | Anti-cd40 antibodies for use in treating autoimmune disease |
WO2020028608A1 (en) | 2018-08-03 | 2020-02-06 | Bristol-Myers Squibb Company | 1H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS AND METHODS AND USES THEREFOR |
WO2020028610A1 (en) | 2018-08-03 | 2020-02-06 | Bristol-Myers Squibb Company | 2H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS AND METHODS AND USES THEREFOR |
WO2020117257A1 (en) | 2018-12-06 | 2020-06-11 | Genentech, Inc. | Combination therapy of diffuse large b-cell lymphoma comprising an anti-cd79b immunoconjugates, an alkylating agent and an anti-cd20 antibody |
WO2020161214A1 (en) | 2019-02-07 | 2020-08-13 | Sanofi | Use of anti-ceacam5 immunoconjugates for treating lung cancer |
EP3693023A1 (en) | 2019-02-11 | 2020-08-12 | Sanofi | Use of anti-ceacam5 immunoconjugates for treating lung cancer |
WO2020191377A1 (en) | 2019-03-21 | 2020-09-24 | Codiak Biosciences, Inc. | Extracellular vesicle conjugates and uses thereof |
WO2020232169A1 (en) | 2019-05-14 | 2020-11-19 | Genentech, Inc. | Methods of using anti-cd79b immunoconjugates to treat follicular lymphoma |
WO2021023657A1 (en) | 2019-08-02 | 2021-02-11 | Immatics Biotechnologies Gmbh | Modified bi specific anti cd3 antibodies |
US11840577B2 (en) | 2019-08-02 | 2023-12-12 | Immatics Biotechnologies Gmbh | Antigen binding proteins specifically binding MAGE-A |
WO2021023658A1 (en) | 2019-08-02 | 2021-02-11 | Immatics Biotechnologies Gmbh | Antigen binding proteins specifically binding mage-a |
WO2021030768A1 (en) | 2019-08-14 | 2021-02-18 | Codiak Biosciences, Inc. | Extracellular vesicles with stat3-antisense oligonucleotides |
WO2021030781A1 (en) | 2019-08-14 | 2021-02-18 | Codiak Biosciences, Inc. | Extracellular vesicles with antisense oligonucleotides targeting kras |
WO2021030769A1 (en) | 2019-08-14 | 2021-02-18 | Codiak Biosciences, Inc. | Extracellular vesicles with nras antisense oligonucleotides |
WO2021030777A1 (en) | 2019-08-14 | 2021-02-18 | Codiak Biosciences, Inc. | Extracellular vesicle linked to molecules and uses thereof |
WO2021030776A1 (en) | 2019-08-14 | 2021-02-18 | Codiak Biosciences, Inc. | Extracellular vesicle-aso constructs targeting stat6 |
WO2021030780A1 (en) | 2019-08-14 | 2021-02-18 | Codiak Biosciences, Inc. | Extracellular vesicle-aso constructs targeting cebp/beta |
WO2021030773A1 (en) | 2019-08-14 | 2021-02-18 | Codiak Biosciences, Inc. | Extracellular vesicle-nlrp3 antagonist |
WO2021076196A1 (en) | 2019-10-18 | 2021-04-22 | Genentech, Inc. | Methods of using anti-cd79b immunoconjugates to treat diffuse large b-cell lymphoma |
WO2021144020A1 (en) | 2020-01-15 | 2021-07-22 | Immatics Biotechnologies Gmbh | Antigen binding proteins specifically binding prame |
US11879004B2 (en) | 2020-02-28 | 2024-01-23 | Genzyme Corporation | Modified binding polypeptides for optimized drug conjugation |
WO2021174034A1 (en) | 2020-02-28 | 2021-09-02 | Genzyme Corporation | Modified binding polypeptides for optimized drug conjugation |
WO2021217051A1 (en) | 2020-04-24 | 2021-10-28 | Genentech, Inc. | Methods of using anti-cd79b immunoconjugates |
WO2022048883A1 (en) | 2020-09-04 | 2022-03-10 | Merck Patent Gmbh | Anti-ceacam5 antibodies and conjugates and uses thereof |
WO2022147463A2 (en) | 2020-12-31 | 2022-07-07 | Alamar Biosciences, Inc. | Binder molecules with high affinity and/ or specificity and methods of making and use thereof |
WO2022170008A2 (en) | 2021-02-05 | 2022-08-11 | Boehringer Ingelheim International Gmbh | Anti-il1rap antibodies |
WO2022178180A1 (en) | 2021-02-17 | 2022-08-25 | Codiak Biosciences, Inc. | Extracellular vesicle linked to a biologically active molecule via an optimized linker and an anchoring moiety |
WO2022233956A1 (en) | 2021-05-05 | 2022-11-10 | Immatics Biotechnologies Gmbh | Antigen binding proteins specifically binding prame |
WO2022241446A1 (en) | 2021-05-12 | 2022-11-17 | Genentech, Inc. | Methods of using anti-cd79b immunoconjugates to treat diffuse large b-cell lymphoma |
WO2023006828A1 (en) | 2021-07-27 | 2023-02-02 | Immatics Biotechnologies Gmbh | Antigen binding proteins specifically binding ct45 |
WO2023019092A1 (en) | 2021-08-07 | 2023-02-16 | Genentech, Inc. | Methods of using anti-cd79b immunoconjugates to treat diffuse large b-cell lymphoma |
WO2023099683A1 (en) | 2021-12-02 | 2023-06-08 | Sanofi | Cea assay for patient selection in cancer therapy |
WO2023099682A1 (en) | 2021-12-02 | 2023-06-08 | Sanofi | Ceacam5 adc–anti-pd1/pd-l1 combination therapy |
WO2023170240A1 (en) | 2022-03-09 | 2023-09-14 | Merck Patent Gmbh | Anti-ceacam5 antibodies and conjugates and uses thereof |
WO2023170239A1 (en) | 2022-03-09 | 2023-09-14 | Merck Patent Gmbh | Methods and tools for conjugation to antibodies |
WO2023172968A1 (en) | 2022-03-09 | 2023-09-14 | Merck Patent Gmbh | Anti-gd2 antibodies, immunoconjugates and therapeutic uses thereof |
Also Published As
Publication number | Publication date |
---|---|
EP0038357A1 (en) | 1981-10-28 |
CA1158557A (en) | 1983-12-13 |
EP0038357A4 (en) | 1982-03-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA1158557A (en) | Hydrolytic enzyme-activatible pro-drugs | |
US5037883A (en) | Synthetic polymeric drugs | |
Dubowchik et al. | Cathepsin B-sensitive dipeptide prodrugs. 2. Models of anticancer drugs paclitaxel (Taxol®), mitomycin C and doxorubicin | |
Dubowchik et al. | Cathepsin B-sensitive dipeptide prodrugs. 1. A model study of structural requirements for efficient release of doxorubicin | |
US7329507B2 (en) | Prodrug compounds with isoleucine | |
US6855689B2 (en) | Enzyme-activated anti-tumor prodrug compounds | |
Chakravarty et al. | Plasmin-activated prodrugs for cancer chemotherapy. 1. Synthesis and biological activity of peptidylacivicin and peptidylphenylenediamine mustard | |
AU2001275525B2 (en) | Tripeptide prodrug compounds | |
US7893023B2 (en) | Prodrugs activated by plasmin and their use in cancer chemotherapy | |
US6620916B1 (en) | Modified physiologically active proteins and medicinal compositions containing the same | |
AU2001266853A1 (en) | Prodrug compounds with an oligopeptide having an isoleucine residue | |
AU2001275525A1 (en) | Tripeptide prodrug compounds | |
JPH05155898A (en) | Amidinophenylalanine derivative and preparation thereof | |
JP2004504358A (en) | Antineoplastic polymer conjugate | |
RU2439077C2 (en) | Protein-binding methotrexate derivatives and medicines containing said derivatives | |
US3330857A (en) | N-carbazoylamino acid intermediates for polypeptides | |
US5776903A (en) | Peptide derivatives usable as zinc endopeptidase 24-15 inhibitors | |
JPS5858342B2 (en) | Dopamine derivatives and medicines containing dopamine derivatives | |
KR100905627B1 (en) | Active Agent Delivery Systems and Methods for Protecting and Administering Active Agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Designated state(s): JP |
|
AL | Designated countries for regional patents |
Designated state(s): CH DE FR GB NL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1980902253 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1980902253 Country of ref document: EP |
|
WWR | Wipo information: refused in national office |
Ref document number: 1980902253 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1980902253 Country of ref document: EP |