WO2005037992A2 - Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates - Google Patents
Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates Download PDFInfo
- Publication number
- WO2005037992A2 WO2005037992A2 PCT/US2004/030917 US2004030917W WO2005037992A2 WO 2005037992 A2 WO2005037992 A2 WO 2005037992A2 US 2004030917 W US2004030917 W US 2004030917W WO 2005037992 A2 WO2005037992 A2 WO 2005037992A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cell
- binding agent
- maytansinoid
- antibody
- ester
- Prior art date
Links
- 0 C[C@@](C(O[C@@](CC(Nc(cc(CC(C)=C*=C[C@]([C@@](C1)(N2)O)OC)cc3*)c3Cl)=O)[C@]3(C)O[C@]3[C@](C)C1OC2=O)=O)N(C)C(***NC(*)=O)=O Chemical compound C[C@@](C(O[C@@](CC(Nc(cc(CC(C)=C*=C[C@]([C@@](C1)(N2)O)OC)cc3*)c3Cl)=O)[C@]3(C)O[C@]3[C@](C)C1OC2=O)=O)N(C)C(***NC(*)=O)=O 0.000 description 5
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
- C07K16/3076—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells against structure-related tumour-associated moieties
- C07K16/3092—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells against structure-related tumour-associated moieties against tumour-associated mucins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
-
- 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
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
- 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
- A61K47/6835—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
-
- 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
- A61K47/6835—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6855—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
-
- 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
- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/04—Amoebicides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
- A61P33/12—Schistosomicides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- a method consistent with the present invention relates to targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker. Another method consistent with the present invention is a method of making the conjugate.
- a composition consistent with the present invention relates to novel cell-binding agent maytansinoid conjugates where the maytansinoid is linked via a non-cleavable linker to the cell- binding agent.
- Another composition consistent with the present invention relates to novel maytansinoid esters.
- Maytansinoids are highly cytotoxic drugs. Maytansine was first isolated by Kupchan et al. from the east African shrub Maytenus serrata and shown to be 100- to 1000-fold more cytotoxic than conventional cancer chemotherapeutic agents like methotrexate, daunorubicin, and vincristine (U.S. Pat. No. 3,896,111). Subsequently, it was discovered that some microbes also produce maytansinoids, such as maytansinol and C-3 esters of maytansinol (U.S. Pat. No.
- esters of group (b) were found to be much more cytotoxic than esters of group (a).
- Maytansine is a mitotic inhibitor. Treatment of L1210 cells in vivo with maytansine has been reported to result in 67% of the cells accumulating in mitosis. Untreated control cells were reported to demonstrate a mitotic index ranging from between 3.2 to 5.8% (Sieber et al., 43 Bibl. Haematol. 495-500 (1976)).
- Maytansine has also been shown to be active in vivo. Tumor growth in the P388 lymphocytic leukemia system was shown to be inhibited over a 50- to 100-fold dosage range, which suggested a high therapeutic index; also significant inhibitory activity could be demonstrated with the L1210 mouse leukemia system, the human Lewis lung carcinoma system and the human B-16 melanocarcinoma system (Kupchan, 33 Ped. Proc 2288-2295 (1974)). [09] Because the maytansinoids are highly cytotoxic, they were expected to be of use in the treatment of many diseases such as cancer. This expectation has yet to be realized. Clinical trials with maytansine were not favorable due to a number of side effects (Issel et al., 5 Cancer Treat.
- a conjugate of maytansinoids linked to the anti-Her2 breast cancer antibody TA.1 via the non-cleavable linker SMCC was shown to be 200- fold less potent than a conjugate of maytansinoids linked to TA.l via a linker having a cleavable disulfide bond (Chari et al., 52 Cancer Res. 127-133 (1992)).
- One aspect of the present invention is a method for targeting a maytansinoid to a selected cell population comprising contacting a cell population or tissue suspected of containing cells from said selected cell population with a cell-binding agent maytansinoid conjugate, wherein one or more maytansinoids is linked to the cell-binding agent via a non-cleavable linker.
- Another aspect of the present invention is a method for treatment of tumors, autoimmune diseases, graft rejections, graft versus host disease, viral infections, parasite infections, and other diseases that can be treated by targeted therapy wherein the targeting agent is a cell-binding agent, said method comprising administering to a subject in need of treatment an effective amount of a cell-binding agent maytansinoid conjugate wherein one or more maytansinoids is linked to the cell-binding agent, or a pharmaceutically acceptable formulation or solvate of said conjugate.
- Another aspect of the present invention is a cell-binding agent maytansinoid conjugate, wherein one or more maytansinoids is linked to a cell-binding agent via a non-cleavable linker.
- Another aspect of the present invention is a composition comprising the above-described conjugate.
- Another aspect of the present invention is a method of making the above-described conjugate.
- Another aspect of the present invention is novel maytansinoid esters.
- FIG. 1 shows the structure of SMCC.
- FIG. 2 shows the structure of DM 1.
- FIG. 3 shows graphically results of a FACS binding assay comparing huC242 antibody to the antibody-maytansinoid conjugate huC242-SMCC-DMl.
- FIG. 4 shows graphically the cytotoxicity of huC242-SMCC-DM 1.
- FIG. 5 shows size exclusion chromatography for huC242-SMCC-DMl .
- FIGS. 6A-C and FIG. 7 show graphically the cytotoxicity of huC242-SMCC-DMl compared to conjugates prepared with disulfide-containing linkers.
- FIGS. 8A-D show graphically the cytotoxicity of SMCC-DM1 conjugates linked to various cell-binding agents.
- FIG. 9 shows graphically the cytotoxicity of antibody-maytansinoid conjugate huC242-
- FIG. 10A shows graphically the antitumor activity of huC242-SMCC-DMl against COLO205 human colon cancer xenografts in SCID mice.
- FIG. 1 OB shows graphically the antitumor activity of huC242-SMCC-DM 1 against SNU16 human gastric tumor xenografts in SCID mice.
- FIG. IOC shows graphically the anti-tumor efficacy of trastuzumab-SMCC-DMl against human MCF7 tumor xenografts in SCID mice.
- FIG. 11 shows graphically plasma clearance rates of huC242-SMCC-DMl compared to conjugates prepared with disulfide-containing linkers.
- FIGS . 12 A-C show graphically results of acute toxicity studies of huC242-SMCC-DM 1 compared to conjugates prepared with disulfide-containing linkers.
- FIG. 13 shows the durability of cell-cycle arrest and cell destroying activity demonstrated by huC242-SMCC-DMl compared to conjugates prepared with disulfide-containing linkers.
- FIGS. 14A-D show the minimal bystander effect activity of huC242-SMCC-DMl compared to conjugates prepared with disulfide-containing linkers.
- FIG. 15 shows representative structures of maleimido-based cross-linking agents.
- FIG. 16 shows representative structures of haloacetyl-based cross-linking agents.
- FIG. 17 shows the structure of antibody-SMCC-DMl conjugates.
- FIG. 18 shows the structure of antibody-SIAB-DMl conjugates.
- FIG. 19 shows the structure of antibody-SMCC-DM4 conjugates.
- FIG. 20 shows the structure of antibody-SIAB-DM4 conjugates.
- FIG. 21 shows the synthesis of a maytansinoid cell-binding agent conjugate linked via a non-S-containing non-cleavable linker.
- FIG. 22 shows graphically cytotoxicity of huC242 -non-S-containing non-cleavable
- FIG. 23 shows graphically results of a FACS binding assay of huC242 -non-S-containing non-cleavable linker-DMl.
- FIG. 24 shows graphically results of a HER2 ECD plate-binding assay comparing trastuzumab antibody to the antibody-maytansinoid conjugate trastuzumab-SMCC-DMl.
- FIG. 25 shows graphically the cytotoxicity and specificity of trastuzumab-SMCC-DMl.
- FIG. 26 shows size exclusion chromatography for trastuzumab-SMCC-DMl .
- FIG. 27 shows graphically results of a HER2 ECD plate-binding assay comparing trastuzumab antibody to the antibody-maytansinoid conjugate trastuzumab-SIAB-DMl.
- FIG. 28 shows graphically the cytotoxicity and specificity of trastuzumab-SIAB-DMl.
- FIG. 29 shows size exclusion chromatography for trastuzumab-SIAB-DMl .
- 5,208,020 demonstrate that potent cytotoxic agents can be created by linking maytansinoids to appropriate cell-binding agents via cleavable linkers, especially cleavable linkers containing disulfide groups.
- Cell-binding agent maytansinoid conjugates permit the full measure of the cytotoxic action of the maytansinoids to be applied in a targeted fashion against unwanted cells only, thereby avoiding side effects due to damage to non-targeted, healthy cells.
- the present inventors have unexpectedly discovered that maytansinoids linked to cell- binding agents via non-cleavable linkers are superior in several important respects to maytansinoids linked via cleavable linkers. In particular, when compared to conjugates containing cleavable linkers, conjugates with non-cleavable linkers show equivalent antitumor activity both in vitro and in vivo, but demonstrate a marked decrease in plasma clearance rate and in toxicity.
- this invention provides an improved method for targeting cells, especially cells that are to be destroyed, such as tumor cells (particularly solid tumor cells), virus infected cells, microorganism infected cells, parasite infected cells, autoimmune cells (cells that produce autoantibodies), activated cells (those involved in graft rejection or graft vs. host disease), or any other type of diseased or abnormal cells, while exhibiting a minimum of side effects.
- tumor cells particularly solid tumor cells
- virus infected cells virus infected cells
- microorganism infected cells include parasite infected cells
- autoimmune cells cells that produce autoantibodies
- activated cells such as graft rejection or graft vs. host disease
- any other type of diseased or abnormal cells while exhibiting a minimum of side effects.
- the conjugate used in the inventive method has one or more maytansinoids linked to a cell-binding agent via a non-cleavable linker.
- a cell- binding agent for example an antibody
- a cross-linking reagent such as SMCC
- a reactive maytansinoid having a thiol group such as DM1
- the maytansinoid can be modified with a cross-linking reagent before being reacted with a cell- binding agent. See, for example, U.S. patent no. 6,441,163 Bl. Suitable Maytansinoids
- Maytansinoids suitable for use in the present invention are well known in the art, and can be isolated from natural sources according to known methods, produced using genetic engineering techniques (see Yu et al., 99 PNAS 7968-7973 (2002)), or prepared synthetically according to known methods.
- Examples of suitable maytansinoids include maytansinol and maytansinol analogues.
- Suitable maytansinol analogues include those having a modified aromatic ring and those having modifications at other positions.
- Suitable maytansinol analogues having a modified aromatic ring include: (1) C-19-dechloro (U.S. Pat. No. 4,256,746) (prepared by LAH reduction of ansamytocin
- Suitable maytansinol analogues having modifications of other positions include: (1) C-9-SH (U.S. Pat. No. 4,424,219) (prepared by the reaction of maytansinol with H 2 S or P 2 S 5 ); (2) C-14-alkoxymethyl(demethoxy/CH 2 OR)(U.S. Pat. No. 4,331,598); (3) C-14-hydroxymethyl or acyloxymethyl (CH 2 OH or CH 2 OAc) (U.S. Pat. No. 4,450,254) (prepared from Nocardia); (4) C-15-hydroxy/acyloxy (U.S. Pat. No.
- Particularly preferred maytansinoids comprising a free thiol group include N-methyl-alanine- containing esters and N-methyl-cysteine-containing esters of maytansinol are C-3 esters of maytansinol and its analogs.
- Preferred esters include N-methyl-alanine-containing esters and N- methyl-cysteine-containing esters of maytansinol. Synthesis of esters of maytansinol having a free thiol group has been previously described, for example in U.S. Patent No. 5,208,020, Chari et al., 52 Cancer Res., 127-131 (1992), and Liu et al., 93 Proc Natl. Acad.
- the maytansinoid contains a sterically hindered thiol group and is represented by formula (II'-L), (II'-D), or (II'-D,L):
- A, B, and D each independently is cyclic alkyl or cyclic alkenyl having 3 to 10 carbon atoms, simple or substituted aryl, or heterocyclic aromatic or heterocycloalkyl radical.
- Ri to R ⁇ are each independently linear alkyl or alkenyl having 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocycloalkyl radical, and in addition, R 2 to Rj 2 can be H.
- 1, m, n, o, p, q, r, s, t, and u are each independently 0 or an integer of from 1 to 5, provided that at least two of 1, m, n, o, p, q, r, s, t and u are not both zero. May represents a maytansinoid that bears a side chain at C-3 hydroxyl, C-14 hydroxymethyl, C-15 hydroxyl or C-20 desmethyl.
- Another maytansinoid useful in the invention is represented by formula (II-L), (II-D), or (II-D,L): D D,L
- Ri to R 8 are each independently linear alkyl or alkenyl having l to 10 carbon atoms, branched or cyclic alkyl or alkenyl having 3 to 10 carbon atoms, phenyl, substituted phenyl, heterocyclic aromatic or heterocycloalkyl radical, and in addition R 2 to R 8 can be H.
- 1, m and n are each independently an integer of from 1 to 5, and in addition n can be 0.
- Ri and R 2 are methyl.
- linear alkyls or alkenyls having 1 to 10 carbon atoms include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, propenyl, butenyl and hexenyl.
- Examples of branched alkyls or alkenyls having 3 to 10 carbon atoms include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 1 -ethyl-propyl, isobutenyl and isopentenyl.
- Examples of cyclic alkyls or alkenyls having from 3 to 10 carbon atoms include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl.
- Simple aryls include aryls having 6 to 10 carbon atoms, and substituted aryls include aryls having 6 to 10 carbon atoms bearing at least one alkyl substituent containing from 1 to 4 carbon atoms, or alkoxy substituent such as methoxy, ethoxy, or a halogen substituent or a nitro substituent.
- Examples of simple aryl that contain 6 to 10 carbon atoms include, but are not limited to, phenyl and naphthyl.
- substituted aryl examples include, but are not limited to, nitrophenyl, dinitrophenyl.
- Heterocyclic aromatic radicals include groups that have a 3 to 10-membered ring containing one or two heteroatoms selected from N, O or S.
- heterocyclic aromatic radicals include, but are not limited to, pyridyl, nitro- pyridyl, pyrollyl, oxazolyl, thienyl, thiazolyl, and furyl.
- Heterocycloalkyl radicals include cyclic compounds, comprising 3 to 10-membered ring systems, containing one or two heteroatoms, selected form N, O or S.
- heterocycloalkyl radicals include, but are not limited to, dihydrofuryl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, piperazinyl,and morpholino.
- Particularly preferred maytansinoids comprising a side chain that contains a sterically hindered thiol bond are maytansinoids N -deacetyl-N- (4-mercapto-l-oxopentyl)-maytansine (termed DM3) and N -deacetyl-N " (4-methyl-4-mercapto-l-oxopentyl)-maytansine (termed DM4).
- DM3 and DM4 are represented by the following structural formulae:
- Cell-binding agents may be of any kind presently known, or that become known and include peptides and non-peptides. Generally, these can be antibodies (especially monoclonal antibodies), lymphokines, hormones, growth factors, vitamins, nutrient-transport molecules (such as transferrin), or any other cell-binding molecule or substance that specifically binds a target.
- cell-binding agents that can be used include: polyclonal and monoclonal antibodies, including fully human antibodies; single chain antibodies (polyclonal and monoclonal); fragments of antibodies (polyclonal and monoclonal) such as Fab, Fab', F(ab') 2 , and Fv
- lymphokines such as IL-2, IL-3, IL-4, IL-6; hormones such as insulin, TRH (thyrotropin releasing hormone), MSH (melanocyte- stimulating hormone), steroid hormones, such as andr ⁇ gens and estrogens; growth factors and colony-stimulating factors such as EGF, TGF-alpha, FGF, VEGF, G- CSF, M-CSF and GM-CSF (Burgess, 5 Immunology Today 155-158 (1984)); transferrin (O'Keefe et al., 260 J. Biol. Chem. 932-937 (1985)); and vitamins, such as folate.
- lymphokines such as IL-2, IL-3, IL-4, IL-6
- hormones such as insulin, TRH (thyrotropin releasing hormone), MSH (melanocyte- stimulating hormone), steroid hormones, such as andr ⁇ gens and estrogens
- growth factors and colony-stimulating factors such as EGF
- Monoclonal antibody techniques allow for the production of extremely specific cell- binding agents in the form of specific monoclonal antibodies.
- Particularly well known in the art are techniques for creating monoclonal antibodies produced by immunizing mice, rats, hamsters or any other mammal with the antigen of interest such as the intact target cell, antigens isolated from the target cell, whole virus, attenuated whole virus, and viral proteins such as viral coat proteins.
- Sensitized human cells can also be used.
- Another method of creating monoclonal antibodies is the use of phage libraries of scFv (single chain variable region), specifically human scFv (see e.g., Griffiths et al., U.S. Patent Nos.
- the monoclonal antibody J5 is a murine IgG2a antibody that is specific for
- CALLA Common Acute Lymphoblastic Leukemia Antigen
- the monoclonal antibody MY9 is a murine IgGi antibody that binds specifically to the
- CD33 antigen J.D. Griffin et al 8 Leukemia Res., 521 (1984)
- AML acute myelogenous leukemia
- the monoclonal antibody anti-B4 interchangeably also called B4, is a murine
- IgG that binds to the CD19 antigen on B cells (Nadler et al, 131 J. Immunol. 244-250 (1983)) and can be used if the target cells are B cells or diseased cells that express this antigen such as in non-Hodgkin's lymphoma or chronic lymphoblastic leukemia.
- HuC242 is a humanized form of the monoclonal antibody C242 that is described in U.S. patent No. 5,552,293 and for which the hybridoma is deposited with the EC ACC identification Number 90012601.
- a humanized form can be prepared by either applying the CDR-grafting methodology (US. Patents Nos. 5,585,089; 5,693,761; and
- HuC242 can also be used to treat CanAg expressing tumors, such as colorectal, pancreatic, non-small cell lung, and gastric cancers.
- the antibody trastuzumab can be used to treat breast and other cancers, such as prostate and ovarian cancers that express the Her2 antigen.
- Anti-IGF-IR antibodies that bind to insulin growth factor receptor are also useful.
- Ovarian cancer and prostate cancer can be successfully targeted with, for example, an anti-MUCl antibody, such as anti-HMFG-2 (Taylor-Papadimitriou et al., 28. Int. J. Cancer 17- 21, 1981) or hCTMOl (56 Cancer Res. 5179-5185, 1996) and an anti-PSMA (prostate-specific membrane antigen), such as J591 (Liu et al. 57 Cancer Res. 3629-3634, 1997) respectively.
- Non-antibody molecules can also be used to target specific cell populations.
- GM-CSF which binds to myeloid cells
- IL-2 which binds to activated T- cells
- MSH which binds to melanocytes
- Folic acid can be used to target the folate receptor expressed on ovarian and other tumors.
- Epidermal growth factor (EGF) can be used to target squamous cancers such as lung and head and neck.
- Somatostatin can be used to target neuroblastomas and other tumor types. Cancers of the breast and testes can be successfully targeted with estrogen (or estrogen analogues) or androgen (or androgen analogues) respectively as cell-binding agents.
- Cross-Linking Reagents [98] The maytansinoid is linked to the cell-binding agent by means of a cross-linking reagent that, when reacted, forms a non-cleavable linker between the maytansinoid and the cell-binding agent.
- a "linker” is any chemical moiety that links a cell-binding agent covalently to a maytansinoid.
- part of the linker is provided by the maytansinoid.
- DM1 a thiol-containing maytansinoid (Fig. 2), is a derivative of the natural maytansinoid, maytansine, and provides part of the linker.
- the side chain at the C-3 hydroxyl group of maytansine ends in -CO-CH 3
- the side chain of DM1 ends in -CO-CH 2 -CH 2 - SH. Therefore the final linker is assembled from two pieces, the cross-linking reagent introduced into the cell-binding agent and the side chain from the DM1.
- Cleavable linkers are linkers that can be cleaved under mild conditions, i.e. conditions under which the activity of the maytansinoid drug is not affected. Many known linkers fall in this category and are described below.
- Disulfide containing linkers are linkers cleavable through disulfide exchange, which can occur under physiological conditions.
- Acid-labile linkers are linkers cleavable at acid pH.
- certain intracellular compartments such as endosomes and lysosomes, have an acidic pH (pH 4-5), and provide conditions suitable to cleave acid-labile linkers.
- Linkers that are photo-labile are useful at the body surface and in many body cavities that are accessible to light. Furthermore, infrared light can penetrate tissue. [104] Some linkers can be cleaved by peptidases. Only certain peptides are readily cleaved inside or outside cells, see e.g. Trouet et al., 79 Proc. Natl. Acad. Sci. USA, 626-629 (1982) and Umemoto et al. 43 Int. J. Cancer, 677-684 (1989). Furthermore, peptides are composed of ⁇ - amino acids and peptidic bonds, which chemically are amide bonds between the carboxylate of one amino acid and the ⁇ -amino group of a second amino acid. Other amide bonds, such as the
- Some linkers can be cleaved by esterases. Again only certain esters can be cleaved by esterases present inside or outside cells. Esters are formed by the condensation of a carboxylic acid and an alcohol. Simple esters are esters produced with simple alcohols, such as aliphatic alcohols, and small cyclic and small aromatic alcohols. For example, the present inventors found no esterase that cleaved the ester at C-3 of maytansine, since the alcohol component of the ester, maytansinol, is very large and complex.
- a non-cleavable linker is any chemical moiety that is capable of linking a maytansinoid to a cell-binding agent in a stable, covalent manner and does not fall under the categories listed above as cleavable linkers.
- non-cleavable linkers are substantially resistant to acid-induced cleavage, light-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage.
- substantially resistant to cleavage means that the chemical bond in the linker or adjoining the linker in at least 80%, preferably at least 85%, more preferably at least 90%, even more preferably at least 95%, and most preferably at least 99% of the cell-binding agent maytansinoid conjugate population remains non-cleavable by an acid, a photolabile-cleaving agent, a peptidase, an esterase, or a chemical or a physiological compound that cleaves the chemical bond (such as a disulfide bond) in a cleavable linker, for within a few hours to several days of treatment with any of the agents described above.
- non-cleavable refers to the ability of the chemical bond in the linker or adjoining to the linker to withstand cleavage induced by an acid, a photolabile-cleaving agent, a peptidase, an esterase, or a chemical or a physiological compound that cleaves a disulfide bond, at conditions under which the maytansinoid or the cell binding agent does not lose its activity.
- a person of ordinary skill in the art would readily distinguish non-cleavable from cleavable linkers.
- An example of an appropriate control for testing whether a linker is substantially resistant to cleavage is a linker with a chemical bond, such as a disulfide bond, that is susceptible to cleavage by any of the agents described above.
- a linker is substantially resistant to cleavage by measuring the stability of the conjugates by ELISA, HPLC, or other suitable means, over a period of time extending from between a few hours to several days, typically 4 hours to 5 days.
- ELISA assays can be used to measure the level of stable conjugate in the plasma concentration.
- Non-cleavable linkers are also characterized in that the in vivo half-life of conjugates comprising non-cleavable linkers is generally about 20% higher than that of conjugates comprising cleavable linkers. In mice, the in vivo half-life of IgG-maytansinoid conjugates linked via non-cleavable linkers is at least 4 days.
- Suitable cross-linking reagents that form non-cleavable linkers between the maytansinoid and the cell-binding agent are well known in the art, and can form non-cleavable linkers that comprise a sulfur atom (such as SMCC) or that are without a sulfur atom.
- Preferred cross-linking reagents that form non-cleavable linkers between the maytansinoid and the cell-binding agent comprise a maleimido- or haloacetyl-based moiety.
- non-cleavable linkers are said to be derived from maleimido- or haloacetyl-based moiety.
- Cross-linking reagents comprising a maleimido-based moiety include N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (SMCC), N- succinimidyl-4-(N-maleimidomethyl)-cyclohexane-l-carboxy-(6-amidocaproate), which is a
- SMPB N-(p-maleimidophenyl)isocyanate
- PMPI N-(p-maleimidophenyl)isocyanate
- Cross-linking reagents comprising a haloacetyl-based moiety include N-succinimidyl-4-
- active esters described in Figs. 15 and 16 are comprised of ⁇ -succinimidyl and sulfosuccinimidyl esters
- other active esters such as ⁇ -hydroxy phthalimidyl esters, ⁇ -hydroxy sulfophthalimidyl esters ortho-nitrophenyl esters, para-nitrophenyl esters, 2,4-dinitrophenyl esters, 3-sulfonyl-4-nitrophenyl esters, 3-carboxy-4-nitrophenyl esters, pentaflurophenyl esters, and sulfonyl tetrafluorophenyl esters can also be used.
- cross-linking reagents form non-cleavable linkers that do not contain a sulfur atom.
- Fig. 21 shows a maytansinoid molecule derivatized with a cross-linking reagent that is derived from an ⁇ , ⁇ -dicarboxylic acid (an alkane or alkene dioic acid wherein the alkane or alkene has 3-24 carbon atoms).
- the cross- linking reagent When reacted with the cell-binding agent, the cross- linking reagent will form a non-sulfur containing non-cleavable linker (non-S-containing non- cleavable linker).
- the maytansinoid molecule of Fig. 21 is made as follows. First a monoester of adipic acid (also known as hexanedioic acid or 1,6-hexanedicarboxylic acid) is prepared by treatment with one equivalent of 2-trimethysilyl ethanol in the presence of dicyclohexylcarbodiimide. Activation of the remaining carboxylic acid group with isobutyl chloroformate, followed by reaction with N-methyl-L-alanine, provides the acylated N-methyl-L-alanine.
- adipic acid also known as hexanedioic acid or 1,6-hexanedicarboxylic acid
- Non-cleavable linkers that do not contain a sulfur atom can also be derived from other dicarboxylic acid based moieties using the method described above.
- Other suitable dicarboxylic acid based moieties include but are not limited to ⁇ , ⁇ -dicarboxylic acids of general formula (IV): HOOC-X,-Y n -Z m -COOH (IV)
- X is a linear or branched alkyl, alkenyl or alkynyl group having 2 to 20 carbon atoms
- Y is a cycloalkyl or cycloalkenyl group bearing 3 to 10 carbon atoms
- Z is a substituted or unsubstituted aromatic group bearing 6 to 10 carbon atoms or a substituted or unsubstituted heterocyclic group wherein the hetero atom is selected from N, O or S, and wherein 1 ,m and n are each 0 or 1, provided that they are all not 0 at the same
- X, Y, Z, 1, m and n are all defined as for formula (IV) above, and further wherein E together with the carbonyl group forms an active ester such as N-hydroxy succinimidyl and sulfosuccinimidyl esters, N-hydroxy phthalimidyl ester, N-hydroxy sulfophthalimidyl ester ortho-nitrophenyl ester, para-nitrophenyl ester, 2,4-dinitrophenyl ester, 3-sulfonyl-4-nitrophenyl ester, 3-carboxy-4-nitrophenyl ester, pentaflurophenyl ester, and sulfonyl tetrafluorophenyl ester.
- an active ester such as N-hydroxy succinimidyl and sulfosuccinimidyl esters, N-hydroxy phthalimidyl ester, N-hydroxy sulfophthalimidyl ester ortho-nitrophenyl ester,
- n represents an integer from 3 to 24, and E has the same definition as for the maytansinoid of formula 5.
- a more preferred embodiment is the derivatized maytansinoid represented by formula 7:
- linear alkyl, alkenyl, or alkynyl groups having 2 to 20 carbon atoms include, but are not limited to, ethyl, propyl, butyl, pentyl, hexyl, propenyl, butenyl, and hexenyl.
- Examples of branched alkyl, alkenyl, or alkynyl groups having 2 to 20 carbon atoms include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 1-ethyl- propyl, isobutenyl, isopentenyl, ethynyl, propynyl (propargyl), 1 -butynyl, 2-butynyl, and 1- hexynyl.
- Examples of cycloalkyl or cycloalkenyl groups having from 3 to 10 carbon atoms include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and cycloheptadienyl.
- aromatic groups that contain 6 to 10 carbon atoms include, but are not limited to, phenyl and naphthyl.
- substituted aromatic groups include, but are not limited to, nitrophenyl and dinitrophenyl.
- Heterocyclic aromatic groups include, but are not limited to, groups that have a 3 to 10- membered ring containing one or two heteroatoms selected from N, O or S.
- Examples of substituted and unsubstituted heterocyclic aromatic groups include, but are not limited to, pyridyl, nitro-pyridyl, pyrollyl, oxazolyl, thienyl, thiazolyl, and furyl.
- Heterocycloalkyl radicals include, but are not limited to, cyclic compounds, comprising 3 to 10-membered ring systems, containing one or two heteroatoms, selected from N, O or S.
- heterocycloalkyl radicals include, but are not limited to, dihydro furyl, tetrahydrofuryl, tetrahydropyrollyl, piperidinyl, piperazinyl, and morpholino.
- Examples of ⁇ , ⁇ -dicarboxylic acids of the general formula HOOC-X ⁇ -Y n -Z m -COOH include, but are not limited to, adipic acid, glutaric acid, pimelic acid, hexene-l,6-dioc acid, pentene-l,5-dioc acid, cyclohexane-dioic acid, and cyclohexene-dioic acid Synthesis of Cytotoxic Conjugates [134] Conjugates of cell-binding agents and maytansinoids can be formed using any techniques presently known or later developed.
- Methods of conjugation of cell-binding agents with maytansinoids generally involve two reaction steps.
- a cell-binding agent such as an antibody
- a cross-linking reagent to introduce one or more, usually 1- 10, reactive groups.
- the modified cell-binding agent is then reacted with one or more thiol- containing maytansinoids to produce a conjugate.
- a thiol-containing maytansinoid can first be modified with a cross-linking reagent, followed by reaction of the modified maytansinoid with a cell-binding agent.
- the thiol-containing maytansinoid can be reacted with the maleimido compounds described in Fig. 15 or with the haloacetyl compounds described in Fig. 16, to give a maytansinoid thioether bearing an active succinimidyl or sulfosuccinimidyl ester.
- Reaction of these maytansinoids containing an activated linker moiety with a cell-binding agent provides another method of producing a non-cleavable cell- binding agent maytansinoid conjugate.
- a maytansinoid that does not contain a sulfur atom can first be derivatized by a dicarboxylic acid based cross-linking reagent, followed by reaction with the cell-binding agent, to form a conjugate in which the maytansinoid is linked to the cell-binding agent via a non-S-containing non-cleavable linker.
- a conjugate in which the maytansinoid is linked to the cell-binding agent via a non-S-containing non-cleavable linker.
- an average of 1-10 maytansinoids per antibody are linked.
- the conjugate can be purified through a Sephadex G-25 column.
- Representational conjugates of the invention are antibody-maytansinoid derivatives, antibody fragment-maytansinoid derivatives, growth factor-maytansinoid conjugates, such as epidermal growth factor (EGF)-maytansinoid derivatives, hormone-maytansinoid conjugates, such as melanocyte stimulating hormone (MSH)-maytansinoid derivatives, thyroid stimulating hormone (TSH)-maytansinoid derivatives, estrogen-maytansinoid derivatives, estrogen analogue-maytansinoid derivatives, androgen-maytansinoid derivatives, androgen analogue- maytansinoid derivatives, androgen analogue- maytansinoid derivatives, and vitamin-maytansinoid conjugates, such as folate maytansinoid.
- EGF epidermal growth factor
- hormone-maytansinoid conjugates such as melanocyte stimulating hormone (MSH)-maytansinoid derivatives, thyroid stimulating hormone (
- Maytansinoid conjugates of antibodies, antibody fragments, protein hormones, protein growth factors and other proteins are made in the same way.
- peptides and antibodies can be modified with the non-cleavable cross-linking reagents mentioned above.
- a solution of an antibody in aqueous buffer may be incubated with a molar excess of an antibody- modifying cross-linking reagent such as succinimidyl 4-(N-maleimidomethyl)-cyclohexane-l- carboxylate (SMCC), sulfo-SMCC, -maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), sulfo-MBS, succinimidyl-iodoacetate, or N-succinimidyl-4-(iodoacetyl)-aminobenzoate (SIAB N-succinimidyl-4-(N-maleimidomethyl)-cyclohexane-l-carboxy-(6-amidocaproate), which is a molar excess of an antibody- modifying cross-linking reagent such as succinimidyl 4-(N-maleimidomethyl)-cyclohexane-l- carboxylate (SM
- succinimidyl ester (KMUA), sulfo-KMUA, ⁇ -maleimidobutyric acid N-succinimidyl ester
- GMBS methyl methacrylate
- EMCS ⁇ -maleimidcaproic acid N-hydroxysuccinimide ester
- the modified antibody is then treated with the thiol-containing maytansinoid (1.25 molar equivalent/maleimido or iodoacetyl group) to produce a conjugate.
- the mixtures are incubated overnight at about 4°C.
- the antibody-maytansinoid conjugates are purified by gel filtration through a Sephadex G-25 column.
- the number of maytansinoid molecules bound per antibody molecule can be determined by measuring spectrophotometrically the ratio of the absorbance at 252 nm and 280 nm. Typically, an average of 1-10 maytansinoids per antibody are linked.
- a preferred method is to modify antibodies with succinimidyl 4-( ⁇ -maleimidomethyl)- cyclohexane-1 -carboxylate (SMCC) to introduce maleimido groups followed by reaction of the modified antibody with a thiol-containing maytansinoid to give a thioether-linked conjugate.
- SMCC succinimidyl 4-( ⁇ -maleimidomethyl)- cyclohexane-1 -carboxylate
- conjugates with 1 to 10 drug molecules per antibody molecule result. Examples of antibody-maytansinoid conjugates are shown in Figs. 17-20.
- estrogen and androgen cell-binding agents such as estradiol and androstenediol can be esterified at the C-17 hydroxy group by reaction with an appropriately protected thiol group-containing carboxylic acid chloride such as 3-S-acetylpropanoyl chloride.
- an appropriately protected thiol group-containing carboxylic acid chloride such as 3-S-acetylpropanoyl chloride.
- Other methods of esterif ⁇ cation can also be employed as described in the literature (Haslam, 36 Tetrahedron 2400-2433 (1980)).
- the protected or free thiol-containing androgen or estrogen can then be reacted with a thiol-containing maytansinoid to produce conjugates.
- the conjugates can be purified by column chromatography on silica gel or by HPLC.
- a particularly preferred method is to modify maytansinol with a cross-linking reagent that results in a linkage that does not contain any sulfur atoms, followed by reaction of the modified maytansinoid with an antibody to produce conjugates.
- Therapeutic efficacy of the cytotoxic conjugates of the invention is to modify maytansinol with a cross-linking reagent that results in a linkage that does not contain any sulfur atoms, followed by reaction of the modified maytansinoid with an antibody to produce conjugates.
- Cell-binding agent maytansinoid conjugates of the invention can be evaluated for their ability to suppress proliferation of various cell lines in vitro.
- cell lines such as the human colon carcinoma line COLO205, the human melanoma cell line A375, the human myeloid leukemia cell line HL60, the human breast carcinoma line SKBR3, or the human epidermoid carcinoma cell line KB can be used for the assessment of cytotoxicity of these conjugates.
- Cells to be evaluated can be exposed to the compounds for 24 hours and the surviving fractions of cells measured in direct assays by known methods. (See, e.g. Goldmacher et al., 135 J. Immunol. 3648-3651 (1985), and Goldmacher et al., 102 J.
- IC 0 values can then be calculated from the results of the assays.
- High cytotoxicity can be defined as exhibiting a toxicity having an IC 50 (the inhibiting concentration of a toxic substance that leaves a surviving fraction of 0.5) of about 10 "8 M or less when measured in vitro with SKBR3 cells upon a 24 hour exposure time to the drug.
- IC 50 the inhibiting concentration of a toxic substance that leaves a surviving fraction of 0.5
- Conjugates of huC242 with DM1 using the cross-linking reagent SMCC are highly potent in destroying antigen positive SKBR3 cells, with an IC 50 value of 3.5 x 10 "12 M.
- antigen negative A375 cells are about 800-fold less sensitive demonstrating that maytansinoid conjugates of the present invention are highly potent and specific.
- conjugates with non-cleavable linkers that show specific activity in vitro are not restricted to the SMCC linker.
- a huC242 conjugate of DM1 synthesized with the non- cleavable linker SIAB showed potent and antigen-specific cytotoxicity in clonogenic assays in vitro (Fig. 9).
- a trastuzumab conjugate of DM1 synthesized with SIAB was also cytotoxic in clonogenic assays (Fig. 28).
- a huC242 -non-S-containing non-cleavable linker-DMl conjugate also demonstrated potent and antigen-specific cytotoxicity in clonogenic assays in vitro (Fig. 22).
- Antibody conjugates with DM1 using the SMCC linker show anti-tumor efficacy against human tumor xenografts in mice (Fig. 10A-C). Marked inhibition of tumor growth was observed upon treatment ofSNUl ⁇ gastric tumor xenografts with huC242-SMCC-DMl (Fig. 10A). This anti-tumor activity is observed at conjugate doses that have no effect on mouse body weight, a measure of drug toxicity. Treatment of mice bearing COLO205 colon carcinoma tumor xenografts with the huC242-SMCC-DMl conjugate resulted in complete regression of tumors, with some mice remaining free of detectable tumors for over 2 months post-treatment (Fig. 10B).
- a trastuzumab-SMCC-DMl conjugate also showed significant tumor regression, in a mouse tumor xenograft model with the MCF-7 breast carcinoma cell line (Fig. IOC).
- Plasma clearance of antibody-maytansinoid conjugate synthesized with the non-cleavable linker SMCC is very slow and comparable to the clearance of antibody alone. This is in sharp contrast to plasma clearance of conjugates prepared with relatively labile disulfide bonds such as huC242-SPP-DMl .
- the half-life for clearance of the SMCC conjugate is approximately 320 hours, while the half-life for the SPP conjugate is in the range of 40-50 hours (Fig. 11).
- the clearance of the antibody component for each type of conjugate is identical, suggesting that the difference in measured conjugate clearance rate is due to the loss of maytansinoid from the antibody conjugate in the case of the SPP-DM1 conjugate.
- the non- cleavable SMCC linkage is therefore much more resistant to maytansinoid-Iinker cleavage activities present in vivo than the SPP-DMl conjugate.
- Maytansinoid conjugates prepared with non-cleavable linkers such as SMCC show an unexpected increased tolerability in mice compared with conjugates prepared with cleavable disulfide linkers. An acute toxicity test with a single intravenous dose was carried out in female CD-I mice.
- Maytansinoid conjugates are thought to impart their cell destroying activity through the inhibition of microtubule polymerization. This inhibition of microtubule polymerization leads to an arrest of the cell cycle principally at G2/M. The antigen-dependent arrest of cells at G2/M by antibody-maytansinoid conjugates can be monitored by flow cytometry analysis (Fig. 13). Treatment of COLO205 cells with huC242-SPP-DMl or huC242-SMCC-DMl conjugate results in a complete G2/M arrest by 6-10 hours.
- the above-described conjugates can be used in a method for targeting maytansinoids to a selected cell population, the method comprising contacting a cell population or tissue suspected of containing the selected cell population with a cell-binding agent maytansinoid conjugate, wherein one or more maytansinoids is covalently linked to the cell-binding agent via a non- cleavable linker and the cell-binding agent binds to cells of the selected cell population.
- the above-described conjugates can also be used in a method of destroying cells, the method comprising contacting the cells with a cell-binding agent maytansinoid conjugate, wherein one or more maytansinoids is covalently linked to the cell-binding agent via a non- cleavable linker and the cell-binding agent binds to the cells.
- the above-described conjugates can also be used in a method of treatment of afflictions including but not limited to malignant tumors, autoimmune diseases, graft rejections, graft versus host disease, viral infections, microorganism infections, and parasite infections, the method comprising administering to a subject in need of treatment an effective amount of a cell-binding agent maytansinoid conjugate, wherein one or more maytansinoids is covalently linked to the cell-binding agent via a non-cleavable linker and the cell-binding agent binds diseased or infected cells of the affliction.
- Examples of medical conditions that can be treated according to the methods of the present invention include but are not limited to malignancy of any type including, for example, cancer of the lung, breast, colon, prostate, kidney, pancreas, ovary, and lymphatic organs; autoimmune diseases, such as systemic lupus, rheumatoid arthritis, and multiple sclerosis; graft rejections, such as renal transplant rejection, liver transplant rejection, lung transplant rejection, cardiac transplant rejection, and bone marrow transplant rejection; graft versus host disease; viral infections, such as CMV infection, HIV infection, AIDS, etc.; and parasite infections, such as giardiasis, amoebiasis, schistosomiasis, and others as determined by one of ordinary skill in the art.
- the methods can be practiced in vitro or in vivo.
- the above-described conjugates can be used in a method of in vitro use to treat, for example, autologous bone marrow cells prior to their transplant into the same patient in order to destroy diseased or malignant cells; bone marrow cells or other tissue prior to their transplantation in order to destroy T cells and other lymphoid cells and prevent graft-versus-host- disease (GVHD); cell cultures in order to destroy all cells except for desired variants that do not express the target antigen; or cell cultures in order to destroy variant cells that express undesired antigen; the method comprising treating the cells with an effective amount of a cell-binding agent maytansinoid conjugate, wherein one or more maytansinoids is covalently linked to the cell-binding agent via a non-cleavable linker and the cell-binding agent binds the cells that are to be destroyed.
- a cell-binding agent maytansinoid conjugate, wherein one or more maytansinoids is covalently linked to the cell-binding agent via
- the treated marrow cells can be stored frozen in liquid nitrogen using standard medical equipment.
- the cytotoxic agent can be supplied as a solution or a lyophilized powder that is tested for sterility and for endotoxin levels. Examples of suitable protocols of conjugate administration are as follows. Conjugates can be given weekly for 4 weeks as an intravenous bolus each week. Bolus doses can be given in 50 to 500 ml of normal saline to which 5 to 10 ml of human serum albumin can be added.
- a cell-binding agent maytansinoid conjugate having at least one maytansinoid linked to a cell-binding agent via a non-cleavable linker, provided that the linker does not comprise a group derived from a cross-linking agent selected from the group consisting of: succinimidyl 4-(N-maleimidomethyl)-cyclohexane-l- carboxylate (SMCC), sulfo-SMCC, m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), sulfo-MBS, and succinimidlyl-iodoacetate when the cell-binding agent is an antibody.
- SMCC succinimidyl 4-(N-maleimidomethyl)-cyclohexane-l- carboxylate
- MBS m-maleimidobenzoyl-N-hydroxysuccinimide ester
- succinimidlyl-iodoacetate when the cell-binding
- the carrier may be a pharmaceutically acceptable carrier, diluent or excipient.
- Suitable carriers, diluents and/or excipients include: (1) Dulbecco's phosphate buffered saline, pH about 7.4, containing or not containing about 1 mg/ml to 25 mg/ml human serum albumin, (2) 0.9% saline (0.9% w/v NaCl), and (3) 5% (w/v) dextrose; and may also contain an antioxidant such as tryptamine and a stabilizing agent such as Tween 20.
- One of the processes of making the cell-binding agent maytansinoid conjugate comprises: (a) providing the cell-binding agent (b) modifying the cell-binding agent with a cross-linking agent, and (c) conjugating the modified cell-binding agent with a maytansinoid or a thiol-containing maytansinoid thereby providing the non-cleavable linker between the cell-binding agent and the maytansinoid or thioLcontaining maytansinoid to produce the conjugate.
- Another process of making the cell-binding agent maytansinoid conjugate comprises: (a) providing the maytansinoid or a thiol-containing maytansinoid, (b) modifying the maytansinoid or thiol-containing maytansinoid with a cross-linking agent to thereby form a non-cleavable linker, and (c) conjugating the modified maytansinoid or thiol-containing maytansinoid with the cell- binding agent, thereby providing the non-cleavable linker between the cell-binding agent and the maytansinoid or thiol-containing maytansinoid to produce the conjugate.
- An additional process of making the cell-binding agent maytansinoid conjugate comprises: (a) providing the maytansinoid, (b) modifying the maytansinoid to provide a non-sulfur-containing maytansinol having an active ester, and
- Solvents used in the following experiments were dimethylsulfoxide (DMSO), dimethylacetamide (DMA), ethanol (EtOH), and lOOmM Ellman's Reagent (DTNB, available from Cayman Chemical) in DMSO.
- DMSO dimethylsulfoxide
- DMA dimethylacetamide
- EtOH ethanol
- DTNB lOOmM Ellman's Reagent
- the antibody was split into two samples; one was modified using a 7.5-fold molar excess of SMCC cross-linker, the other with a 8.5-fold molar excess of SMCC cross-linker. Samples were reacted at 8 mg/mL antibody. The reactions were carried out in Buffer A (95% v/v) with
- Trastuzumab antibody was obtained from Genentech for conjugation to DM1 using the non-cleavable heterobifunctional cross-linking reagent SMCC.
- the antibody was buffer- exchanged from 50 mM potassium phosphate/2 mM EDTA, pH 6.0 into 50 mM potassium phosphate/50 mM sodium chloride/2 mM EDTA, pH 6.5 (Buffer A).
- the antibody was then reacted with 7.5-fold molar excess SMCC linker and purified by Sephadex G25 resin before it was conjugated with DM1.
- the final conjugate was again purified by Sephadex G25 resin.
- the resulting conjugate contained 3.1 moles of DM1 per mole of antibody.
- a 10 mM solution of DM1 (free thiol form) was prepared in DMA (7.37 mg/mL) (Fig, 2).
- the absorbance of dilutions of the stock solution in EtOH was measured at 280 nm.
- the concentration of stock DM1 was calculated by using a molar extinction coefficient of 5700 M " 'cm "1 at 280 nm.
- the concentration of free -SH in the stock DM1 preparation was measured using Ellman's reagent (DTNB). Dilutions of the stock solution were prepared in Assay buffer made to 3% (v/v) DMA, and then 100 mM DTNB in DMSO (1/100 th volume) was added.
- the trastuzumab-SMCC reaction mixture was gel-filtered through a 1.5 x 4.9 cm prepacked column of Sephadex G25 resin equilibrated in Buffer A. The load and elution volumes were according to manufacturer's instructions (Amersham Biosciences). The concentration of the modified antibody solution was assayed spectrophotometrically using the extinction coefficient described above. The yield of modified antibody was 88 % based on protein concentration.
- Conjugation of Trastuzumab-SMCC with DM1 [202] The modified antibody was reacted with a 1.7-fold excess of DM1 over linker (assuming 5 linkers per antibody).
- the DMl/antibody ratio was found to be 3.13 and the conjugation step yield was 95.7%.
- the overall yield of conjugated trastuzumab was 84% based on the starting antibody.
- the resulting conjugate was analyzed for binding, cytotoxicity, specificity, extent of aggregation and free drug content.
- the antibody was modified using a 7.0-fold molar excess of SIAB at 20 mg/mL antibody.
- the reaction was carried out in Buffer A (95% v/v) with DMSO (5% v/v) for 2 hours at room temperature with stirring in the dark. e. G25 Chromatography to remove excess SIAB
- trastuzumab antibody and trastuzumab-SIAB-DMl were compared using the HER2 ECD plate binding assay provided by Genentech. The results are shown in Fig. 27. Naked trastuzumab and trastuzumab-SIAB-DMl had similar binding affinities (1.2x 10 "10 M for the antibody and 1.9x 10 "10 M apparent K D for the conjugate). b.
- DM1 is 4.7 (in ETOH) while ⁇ 52 / ⁇ 280 for this cross-linking reagent solution (in pH 7.5 buffer)
Priority Applications (27)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020137020144A KR101476082B1 (ko) | 2003-10-10 | 2004-10-12 | 메이탠시노이드 화합물 |
PL04793896T PL1689846T3 (pl) | 2003-10-10 | 2004-10-12 | Koniugaty maytansinoidu dm1 połączonego nierozłączalnym łącznikiem z przeciwciałem trastuzumab i ich zastosowanie w leczeniu nowotworów |
KR1020137023561A KR101573124B1 (ko) | 2003-10-10 | 2004-10-12 | 비절단성 링커를 통해 연결된 세포결합물질 메이탠시노이드 접합체, 및 상기 접합체 생산방법 |
EA200600752A EA010508B1 (ru) | 2003-10-10 | 2004-10-12 | Способ прицельного воздействия на определенные популяции клеток с помощью конъюгатов из майтансиноида и агента клеточного связывания, соединенных через нерасщепляемый линкер, конъюгаты и способы получения таких конъюгатов |
NZ545195A NZ545195A (en) | 2003-10-10 | 2004-10-12 | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates |
ES04793896T ES2404304T3 (es) | 2003-10-10 | 2004-10-12 | Conjugados de maitansinoide DM1 con anticuerpo trastuzumab, unidos mediante un conector no escindible, y su uso en el tratamiento de tumores |
NO20150450A NO347360B1 (no) | 2003-10-10 | 2004-10-12 | Cellebindingsmiddelmaytansinoid-konjugat med formel trastuzumab-SMCC-DM1 eller trastuzumab-SIABDM1, fremgangsmåte for fremstilling av disse og en in vitro fremgangsmåte for å styre maytansinoider til en valgt cellepopulasjon eller for å eliminere celler, samt anvendelse. |
CN200480026459.3A CN101087611B (zh) | 2003-10-10 | 2004-10-12 | 用经不可切割接头连接的细胞结合剂美登木素生物碱偶联物靶向特定细胞群的方法、所述偶联物和制备所述偶联物的方法 |
JP2006533951A JP2007520450A (ja) | 2003-10-10 | 2004-10-12 | 非開裂リンカーを介して連結した細胞結合物質メイタンシノイド複合体を用いて特定の細胞集団を標的とする方法、前記複合体、および前記複合体の製造法 |
CA2542128A CA2542128C (en) | 2003-10-10 | 2004-10-12 | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates |
DK04793896.4T DK1689846T3 (da) | 2003-10-10 | 2004-10-12 | Konjugater af maytansinoid DM1 med antistof trastuzumab, bundet via en ikke-spaltelig linker, og anvendelse heraf i tumorbehandling |
SI200432024T SI1689846T1 (en) | 2003-10-10 | 2004-10-12 | Conjugates of maytansinoid DM1 with antibody trastuzumab, linked through a non-cleavable linker, and its use in the treatment of tumours |
BRPI0415448A BRPI0415448A8 (pt) | 2003-10-10 | 2004-10-12 | método de alvejar populações de célula específica empregando-se conjugados de maytansinoid de agente de ligação celular ligados por meio de um ligante não-clivável, os referidos conjugados, e métodos de preparação dos referidos conjugados |
EP04793896A EP1689846B1 (en) | 2003-10-10 | 2004-10-12 | Conjugates of maytansinoid DM1 with antibody trastuzumab, linked through a non-cleavable linker, and its use in the treatment of tumours |
KR1020127004142A KR101343676B1 (ko) | 2003-10-10 | 2004-10-12 | 메이탠시노이드 화합물 |
AU2004282491A AU2004282491C1 (en) | 2003-05-14 | 2004-10-12 | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates |
IL173625A IL173625A (en) | 2003-10-10 | 2006-02-09 | Coupler connectors for cell and methanesinoid and methods for using them |
NO20061772A NO337458B1 (no) | 2003-10-10 | 2006-04-21 | Konjugater av maytansinoid DM1 med antistoffet trastuzumab, bundet via en ikke-kløyvbar linker, og dets anvendelse ved behandling av tumorer |
AU2010212291A AU2010212291C1 (en) | 2003-05-14 | 2010-08-12 | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates |
IL214788A IL214788A0 (en) | 2003-10-10 | 2011-08-22 | Cell binding agent maytansinoid conjugates and methods for using the same |
HRP20130412TT HRP20130412T1 (en) | 2003-10-10 | 2013-05-09 | Conjugates of maytansinoid dm1 with antibody trastuzumab, linked through a non-cleavable linker, and its use in the treatment of tumours |
LU92336C LU92336I2 (fr) | 2003-10-10 | 2013-12-16 | Trastuzumab emtansine et ses dérivés pharmaceutiquement acceptables (KADCYLA) |
CY2014002C CY2014002I1 (el) | 2003-10-10 | 2014-01-16 | Προϊοντα συζευξης μεϋτανσινοειδους dm1 με αντισωμα trastuzumab, συνδεδεμενα μεσω μη-διασπασιμου συνδετηρα και χρηση αυτων στη θεραπεια ογκων |
IL235253A IL235253B (en) | 2003-10-10 | 2014-10-21 | Active esters of maytansinoid thioether compounds |
NO2016001C NO2016001I1 (no) | 2003-10-10 | 2016-01-26 | Trastuzumab emtansin |
NO20160447A NO20160447A1 (no) | 2003-10-10 | 2016-03-16 | Fremgangsmåte for målsøking av spesifikke cellepopulasjoner ved å benytte cellebindings-middelmaytansinoidkonjugater bundet via en ikke-kløyvbar linker, nevnte konjugater og fremstilling av nevnte konjugater |
IL246605A IL246605A (en) | 2003-10-10 | 2016-07-05 | Coupler connectors for cell and methanesinoid and methods for using them |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US50990103P | 2003-10-10 | 2003-10-10 | |
US60/509,901 | 2003-10-10 | ||
US10/960,602 | 2004-10-08 | ||
US10/960,602 US8088387B2 (en) | 2003-10-10 | 2004-10-08 | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2005037992A2 true WO2005037992A2 (en) | 2005-04-28 |
WO2005037992A3 WO2005037992A3 (en) | 2009-04-23 |
Family
ID=34467962
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2004/030917 WO2005037992A2 (en) | 2003-05-14 | 2004-10-12 | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates |
Country Status (25)
Cited By (84)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005117986A2 (en) * | 2004-06-01 | 2005-12-15 | Genentech, Inc. | Antibody drug conjugates and methods |
WO2006086733A3 (en) * | 2005-02-11 | 2007-06-07 | Immunogen Inc | Process for preparing maytansinoid antibody conjugates |
EP1942944A2 (en) * | 2005-10-31 | 2008-07-16 | Genentech, Inc. | Macrocyclic depsipeptide antibody-drug conjugates and methods |
JP2009506032A (ja) * | 2005-08-24 | 2009-02-12 | イムノゲン インコーポレーティッド | メイタンシノイド(maytansinoid)抗体複合体の調製方法 |
WO2010120561A1 (en) | 2009-04-01 | 2010-10-21 | Genentech, Inc. | Anti-fcrh5 antibodies and immunoconjugates and methods of use |
WO2010141902A2 (en) | 2009-06-04 | 2010-12-09 | Novartis Ag | METHODS FOR IDENTIFICATION OF SITES FOR IgG CONJUGATION |
WO2011153346A1 (en) | 2010-06-03 | 2011-12-08 | Genentech, Inc. | Immuno-pet imaging of antibodies and immunoconjugates and uses therefor |
WO2011156328A1 (en) | 2010-06-08 | 2011-12-15 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
US8088378B2 (en) | 2007-07-16 | 2012-01-03 | Genetech Inc. | Anti-CD79B antibodies and immunoconjugates and methods of use |
EP2447282A2 (en) | 2006-05-30 | 2012-05-02 | Genentech, Inc. | Anti-CD22 Antibodies, their Immunoconjugates and uses thereof |
WO2012074757A1 (en) | 2010-11-17 | 2012-06-07 | Genentech, Inc. | Alaninyl maytansinol antibody conjugates |
EP2486023A1 (en) * | 2009-10-06 | 2012-08-15 | ImmunoGen, Inc. | Potent conjugates and hydrophilic linkers |
US20120226026A1 (en) * | 2008-04-30 | 2012-09-06 | Immunogen, Inc. | Potent conjugates and hydrophilic linkers |
WO2012154809A1 (en) | 2011-05-09 | 2012-11-15 | University Of Virginia Patent Foundation | Compositions and methods for treating cancer |
WO2012162561A2 (en) | 2011-05-24 | 2012-11-29 | Zyngenia, Inc. | Multivalent and monovalent multispecific complexes and their uses |
WO2012135522A3 (en) * | 2011-03-29 | 2013-01-24 | Immunogen, Inc. | Process for manufacturing conjugates of improved homogeneity |
WO2013063001A1 (en) | 2011-10-28 | 2013-05-02 | Genentech, Inc. | Therapeutic combinations and methods of treating melanoma |
WO2013130093A1 (en) | 2012-03-02 | 2013-09-06 | Genentech, Inc. | Biomarkers for treatment with anti-tubulin chemotherapeutic compounds |
CN103328505A (zh) * | 2010-10-29 | 2013-09-25 | 伊缪诺金公司 | 非拮抗性egfr结合分子及其免疫偶联物 |
EP2641618A2 (en) | 2007-07-16 | 2013-09-25 | Genentech, Inc. | Humanized anti-CD79B antibodies and immunoconjugates and methods of use |
EP2657253A2 (en) | 2008-01-31 | 2013-10-30 | Genentech, Inc. | Anti-CD79b antibodies and immunoconjugates and methods of use |
KR101343676B1 (ko) | 2003-10-10 | 2013-12-20 | 이뮤노젠 아이엔씨 | 메이탠시노이드 화합물 |
US8663643B2 (en) | 2008-03-18 | 2014-03-04 | Genentech, Inc. | Combinations of an anti-HER2 antibody-drug conjugate and chemotherapeutic agents, and methods of use |
US8765917B2 (en) | 2010-03-12 | 2014-07-01 | Immunogen, Inc. | CD37-binding molecules and immunoconjugates thereof |
US8795673B2 (en) | 2011-03-29 | 2014-08-05 | Immunogen, Inc. | Preparation of maytansinoid antibody conjugates by a one-step process |
WO2014150937A1 (en) * | 2013-03-15 | 2014-09-25 | Novartis Ag | Antibody drug conjugates |
US8877706B2 (en) * | 2012-12-21 | 2014-11-04 | Bio-Thera Solutions Ltd., Co. | Maytansinoid derivatives |
US8883979B2 (en) | 2012-08-31 | 2014-11-11 | Bayer Healthcare Llc | Anti-prolactin receptor antibody formulations |
WO2014182970A1 (en) | 2013-05-08 | 2014-11-13 | Zymeworks Inc. | Bispecific her2 and her3 antigen binding constructs |
WO2014208987A1 (ko) | 2013-06-24 | 2014-12-31 | 한화케미칼 주식회사 | 안정성이 개선된 항체-약물 결합체 및 이의 용도 |
WO2014160160A3 (en) * | 2013-03-13 | 2015-01-08 | Novartis Ag | Antibody drug conjugates and corresponding antibodies |
WO2015009740A2 (en) | 2013-07-15 | 2015-01-22 | Cell Signaling Technology, Inc. | Anti-mucin 1 binding agents and uses thereof |
EP2845866A1 (en) | 2006-10-27 | 2015-03-11 | Genentech, Inc. | Antibodies and immunoconjugates and uses therefor |
WO2015073721A1 (en) | 2013-11-13 | 2015-05-21 | Zymeworks Inc. | Monovalent antigen binding constructs targeting egfr and/or her2 and uses thereof |
US9085630B2 (en) | 2002-11-15 | 2015-07-21 | Genentech, Inc. | Compositions and methods for the treatment of tumor of hematopoietic origin |
WO2015110935A1 (en) | 2014-01-27 | 2015-07-30 | Pfizer Inc. | Bifunctional cytotoxic agents |
WO2015113476A1 (zh) | 2014-01-29 | 2015-08-06 | 上海恒瑞医药有限公司 | 配体-细胞毒性药物偶联物、其制备方法及其应用 |
WO2016040856A2 (en) | 2014-09-12 | 2016-03-17 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
US9345661B2 (en) | 2009-07-31 | 2016-05-24 | Genentech, Inc. | Subcutaneous anti-HER2 antibody formulations and uses thereof |
US9376500B2 (en) | 2009-06-03 | 2016-06-28 | Immunogen, Inc. | Conjugation methods |
US9415118B2 (en) | 2013-03-13 | 2016-08-16 | Novartis Ag | Antibody drug conjugates |
US9447189B2 (en) | 2011-04-01 | 2016-09-20 | Immunogen, Inc. | CD37-binding molecules and immunoconjugates thereof |
WO2016151432A1 (en) | 2015-03-20 | 2016-09-29 | Pfizer Inc. | Bifunctional cytotoxic agents containing the cti pharmacophore |
EP3088004A1 (en) | 2004-09-23 | 2016-11-02 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
EA025786B1 (ru) * | 2011-03-29 | 2017-01-30 | Иммуноджен, Инк. | Способ производства конъюгатов с улучшенной гомогенностью |
EP3164420A4 (en) * | 2014-06-30 | 2018-05-23 | Tarveda Therapeutics, Inc. | Targeted conjugates and particles and formulations thereof |
EP3160518A4 (en) * | 2014-06-30 | 2018-05-23 | Tarveda Therapeutics, Inc. | Targeted conjugates and particles and formulations thereof |
US10035817B2 (en) | 2012-10-04 | 2018-07-31 | Immunogen, Inc. | Method of purifying cell-binding agent-cytotoxic agent conjugates with a PVDF membrane |
EP3316863A4 (en) * | 2015-06-30 | 2019-02-13 | Tarveda Therapeutics, Inc. | DIRECTED CONJUGATES AND PARTICLES AND FORMULATIONS THEREOF |
EP3308801A4 (en) * | 2015-06-09 | 2019-02-27 | XDCExplorer (Shanghai) Co., Ltd. | ANTIBODY-MEDICINAL CONJUGATE, INTERMEDIATE, PREPARATION METHOD, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF |
US10280227B2 (en) | 2009-09-11 | 2019-05-07 | Genentech, Inc. | Highly concentrated pharmaceutical formulations |
US10494423B2 (en) | 2011-06-21 | 2019-12-03 | Immunogen, Inc. | Maytansinoid derivatives with peptide linker and conjugates thereof |
US10538535B2 (en) | 2017-04-27 | 2020-01-21 | Pharma Mar, S.A. | Antitumoral compounds |
WO2020022363A1 (ja) | 2018-07-25 | 2020-01-30 | 第一三共株式会社 | 抗体-薬物コンジュゲートの効果的な製造方法 |
US10548881B2 (en) | 2016-02-23 | 2020-02-04 | Tarveda Therapeutics, Inc. | HSP90 targeted conjugates and particles and formulations thereof |
US10584181B2 (en) | 2009-12-04 | 2020-03-10 | Genentech, Inc. | Methods of making and using multispecific antibody panels and antibody analog panels |
WO2020063676A1 (zh) | 2018-09-26 | 2020-04-02 | 江苏恒瑞医药股份有限公司 | 依喜替康类似物的配体-药物偶联物及其制备方法和应用 |
US10640508B2 (en) | 2017-10-13 | 2020-05-05 | Massachusetts Institute Of Technology | Diazene directed modular synthesis of compounds with quaternary carbon centers |
CN111195353A (zh) * | 2020-03-19 | 2020-05-26 | 烟台迈百瑞国际生物医药有限公司 | 一种美登素类抗体药物偶联物及其应用 |
WO2020216947A1 (en) | 2019-04-24 | 2020-10-29 | Heidelberg Pharma Research Gmbh | Amatoxin antibody-drug conjugates and uses thereof |
US10835616B2 (en) | 2014-10-14 | 2020-11-17 | Polytherics Limited | Process for the conjugation of a peptide or protein with a reagent comprising a leaving group including a portion of PEG |
US10918735B2 (en) | 2012-12-04 | 2021-02-16 | Massachusetts Institute Of Technology | Substituted pyrazino[1′,2′:1,5]pyrrolo[2,3-b]indole-1,4-diones for cancer treatment |
US10918627B2 (en) | 2016-05-11 | 2021-02-16 | Massachusetts Institute Of Technology | Convergent and enantioselective total synthesis of Communesin analogs |
WO2021052402A1 (zh) | 2019-09-18 | 2021-03-25 | 四川百利药业有限责任公司 | 一种喜树碱衍生物及其偶联物 |
US11000510B2 (en) | 2014-09-23 | 2021-05-11 | Genentech, Inc. | Methods of using anti-CD79b immunoconjugates |
US11033628B1 (en) | 2005-10-14 | 2021-06-15 | Phigenix, Inc. | Targeting PAX2 for the treatment of breast cancer |
WO2021148003A1 (zh) | 2020-01-22 | 2021-07-29 | 上海森辉医药有限公司 | 艾日布林衍生物的药物偶联物、其制备方法及其在医药上的应用 |
US11104740B2 (en) | 2015-08-28 | 2021-08-31 | Debiopharm International, S.A. | Antibodies and assays for detection of CD37 |
WO2021190602A1 (zh) | 2020-03-25 | 2021-09-30 | 江苏恒瑞医药股份有限公司 | 一种抗体药物偶联物的制备方法 |
WO2021190581A1 (zh) | 2020-03-25 | 2021-09-30 | 江苏恒瑞医药股份有限公司 | 一种含抗体药物偶联物的药物组合物及其用途 |
US11160871B2 (en) | 2015-10-28 | 2021-11-02 | Tarveda Therapeutics, Inc. | SSTR-targeted conjugates and particles and formulations thereof |
US11224663B2 (en) | 2013-05-31 | 2022-01-18 | Pharma Mar, S.A. | Antibody drug conjugates |
US11278629B2 (en) | 2016-11-02 | 2022-03-22 | Debiopharm International, S.A. | Methods for improving anti-CD37 immunoconjugate therapy |
US11395796B2 (en) | 2015-06-08 | 2022-07-26 | Debiopharm International, S.A. | Anti-CD37 immunoconjugate and anti-CD20 antibody combinations |
WO2022217022A1 (en) | 2021-04-10 | 2022-10-13 | Profoundbio Us Co. | Folr1 binding agents, conjugates thereof and methods of using the same |
WO2022226317A1 (en) | 2021-04-23 | 2022-10-27 | Profoundbio Us Co. | Anti-cd70 antibodies, conjugates thereof and methods of using the same |
US11535634B2 (en) | 2019-06-05 | 2022-12-27 | Massachusetts Institute Of Technology | Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof |
US11555019B2 (en) | 2019-07-10 | 2023-01-17 | Cybrexa 3, Inc. | Peptide conjugates of microtubule-targeting agents as therapeutics |
US11634508B2 (en) | 2019-07-10 | 2023-04-25 | Cybrexa 2, Inc. | Peptide conjugates of cytotoxins as therapeutics |
WO2023092099A1 (en) | 2021-11-19 | 2023-05-25 | Ardeagen Corporation | Gpc3 binding agents, conjugates thereof and methods of using the same |
WO2023170216A1 (en) | 2022-03-11 | 2023-09-14 | Astrazeneca Ab | A SCORING METHOD FOR AN ANTI-FRα ANTIBODY-DRUG CONJUGATE THERAPY |
WO2023169896A1 (en) | 2022-03-09 | 2023-09-14 | Astrazeneca Ab | BINDING MOLECULES AGAINST FRα |
US11779663B2 (en) | 2016-02-04 | 2023-10-10 | Hangzhou Dac Biotech Co., Ltd. | Specific conjugation linkers, specific immunoconjugates thereof, methods of making and uses such conjugates thereof |
US11932650B2 (en) | 2017-05-11 | 2024-03-19 | Massachusetts Institute Of Technology | Potent agelastatin derivatives as modulators for cancer invasion and metastasis |
Families Citing this family (206)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2289549A3 (en) | 1999-10-01 | 2011-06-15 | Immunogen, Inc. | Immunoconjugates for treating cancer |
US7097840B2 (en) * | 2000-03-16 | 2006-08-29 | Genentech, Inc. | Methods of treatment using anti-ErbB antibody-maytansinoid conjugates |
US20100056762A1 (en) | 2001-05-11 | 2010-03-04 | Old Lloyd J | Specific binding proteins and uses thereof |
PT2163256E (pt) | 2001-05-11 | 2015-11-20 | Ludwig Inst For Cancer Res Ltd | Proteínas de ligação específica e suas utilizações |
US20090068178A1 (en) * | 2002-05-08 | 2009-03-12 | Genentech, Inc. | Compositions and Methods for the Treatment of Tumor of Hematopoietic Origin |
NZ571508A (en) * | 2002-05-24 | 2010-05-28 | Schering Corp | Neutralizing human anti-IGFR antibody |
US7276497B2 (en) * | 2003-05-20 | 2007-10-02 | Immunogen Inc. | Cytotoxic agents comprising new maytansinoids |
US7375078B2 (en) * | 2004-02-23 | 2008-05-20 | Genentech, Inc. | Heterocyclic self-immolative linkers and conjugates |
US20060045877A1 (en) * | 2004-08-30 | 2006-03-02 | Goldmakher Viktor S | Immunoconjugates targeting syndecan-1 expressing cells and use thereof |
WO2006060533A2 (en) | 2004-12-01 | 2006-06-08 | Genentech, Inc. | Conjugates of 1, 8-bis-naphthalimides with an antibody |
US20110166319A1 (en) * | 2005-02-11 | 2011-07-07 | Immunogen, Inc. | Process for preparing purified drug conjugates |
AU2006236637B2 (en) * | 2005-04-15 | 2012-09-06 | Merck Sharp & Dohme Corp. | Methods and compositions for treating or preventing cancer |
JP2006316040A (ja) | 2005-05-13 | 2006-11-24 | Genentech Inc | Herceptin(登録商標)補助療法 |
TWI478938B (zh) | 2006-01-20 | 2015-04-01 | Genentech Inc | 抗-ephrinb2抗體及使用該抗體的方法 |
AR059851A1 (es) | 2006-03-16 | 2008-04-30 | Genentech Inc | Anticuerpos de la egfl7 y metodos de uso |
CN101711284A (zh) | 2007-01-25 | 2010-05-19 | 达娜-法勃肿瘤研究所 | 抗egfr抗体在治疗egfr突变体介导的疾病中的用途 |
CN101688229B (zh) | 2007-03-15 | 2013-06-12 | 路德维格癌症研究所 | 包含egfr抗体和src抑制剂的组合物及其在制备用于治疗哺乳动物癌症的药物中的用途 |
US7960139B2 (en) | 2007-03-23 | 2011-06-14 | Academia Sinica | Alkynyl sugar analogs for the labeling and visualization of glycoconjugates in cells |
CA2680237C (en) | 2007-03-27 | 2018-11-06 | Sea Lane Biotechnologies, Llc | Constructs and libraries comprising antibody surrogate light chain sequences |
US20090011060A1 (en) * | 2007-07-06 | 2009-01-08 | Peter Koepke | Campsiandra angustifolia extract and methods of extracting and using such extract |
CN108424454B (zh) | 2007-08-14 | 2022-05-31 | 路德维格癌症研究所有限公司 | 靶向egf受体的单克隆抗体175及其衍生物和用途 |
JP2010536790A (ja) | 2007-08-17 | 2010-12-02 | パーデュー・リサーチ・ファウンデーション | Psma結合性リガンド−リンカー結合体及び使用方法 |
US7879369B2 (en) | 2007-09-18 | 2011-02-01 | Selvamedica, Llc | Combretum laurifolium Mart. extract and methods of extracting and using such extract |
WO2009134870A1 (en) * | 2008-04-30 | 2009-11-05 | Immunogen, Inc. | Potent cell-binding agent drug conjugates |
US20100092495A1 (en) * | 2008-04-30 | 2010-04-15 | Immunogen Inc. | Potent cell-binding agent drug conjugates |
MY157165A (en) | 2008-04-30 | 2016-05-13 | Immunogen Inc | Cross-linkers and their uses |
JP5986745B2 (ja) | 2008-07-15 | 2016-09-06 | アカデミア シニカAcademia Sinica | Ptfe様のアルミニウム・コート・ガラススライド上のグリカンアレイおよび関連する方法 |
NZ594177A (en) | 2009-02-05 | 2014-02-28 | Immunogen Inc | Novel benzodiazepine derivatives |
MX345909B (es) | 2009-03-25 | 2017-02-22 | Genentech Inc | Anticuerpos anti-fgfr3 y métodos que los utilizan. |
WO2010112193A1 (en) | 2009-04-02 | 2010-10-07 | Roche Glycart Ag | Multispecific antibodies comprising full length antibodies and single chain fab fragments |
CA2759502C (en) | 2009-04-29 | 2021-02-09 | Bio-Rad Laboratories, Inc. | Purification of immunoconjugates |
JP2012526839A (ja) | 2009-05-13 | 2012-11-01 | シー レーン バイオテクノロジーズ, エルエルシー | インフルエンザウイルスに対する中和分子 |
IN2012DN03025A (US07989598-20110802-C00006.png) | 2009-09-09 | 2015-07-31 | Ct Se Llc | |
AU2010296018B2 (en) | 2009-09-16 | 2016-05-05 | Genentech, Inc. | Coiled coil and/or tether containing protein complexes and uses thereof |
NZ599456A (en) * | 2009-10-26 | 2014-06-27 | Nestec Sa | Assays for the detection of anti-tnf drugs and autoantibodies |
US11377485B2 (en) | 2009-12-02 | 2022-07-05 | Academia Sinica | Methods for modifying human antibodies by glycan engineering |
US10087236B2 (en) | 2009-12-02 | 2018-10-02 | Academia Sinica | Methods for modifying human antibodies by glycan engineering |
US20110165155A1 (en) * | 2009-12-04 | 2011-07-07 | Genentech, Inc. | Methods of treating metastatic breast cancer with trastuzumab-mcc-dm1 |
PL2516465T3 (pl) | 2009-12-23 | 2016-11-30 | Przeciwciała anty-bv8 i ich zastosowania | |
AU2011215900A1 (en) | 2010-02-10 | 2012-07-26 | Immunogen, Inc. | CD20 antibodies and uses thereof |
AU2011221226A1 (en) | 2010-02-23 | 2012-08-16 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
RU2740479C2 (ru) | 2010-02-24 | 2021-01-14 | Иммьюноджен, Инк. | Антитела против рецептора фолиевой кислоты 1, их иммуноконъюгаты и использование |
US9951324B2 (en) | 2010-02-25 | 2018-04-24 | Purdue Research Foundation | PSMA binding ligand-linker conjugates and methods for using |
TW201138821A (en) | 2010-03-26 | 2011-11-16 | Roche Glycart Ag | Bispecific antibodies |
US10338069B2 (en) | 2010-04-12 | 2019-07-02 | Academia Sinica | Glycan arrays for high throughput screening of viruses |
CA2796633C (en) | 2010-04-23 | 2020-10-27 | Genentech, Inc. | Production of heteromultimeric proteins |
WO2012019024A2 (en) | 2010-08-04 | 2012-02-09 | Immunogen, Inc. | Her3-binding molecules and immunoconjugates thereof |
RU2013110875A (ru) | 2010-08-24 | 2014-09-27 | Ф.Хоффманн-Ля Рош Аг | БИСПЕЦИФИЧЕСКИЕ АНТИТЕЛА, СОДЕРЖАЩИЕ СТАБИЛИЗИРОВАННЫЙ ДИСУЛЬФИДОМ ФРАГМЕНТ Fv |
JP5828901B2 (ja) | 2010-10-29 | 2015-12-09 | イミュノジェン, インコーポレイテッド | 新規egfr結合分子およびその免疫抱合体 |
SG191153A1 (en) | 2010-12-23 | 2013-07-31 | Hoffmann La Roche | Polypeptide-polynucleotide-complex and its use in targeted effector moiety delivery |
PT2668209T (pt) | 2011-01-24 | 2021-04-07 | Gilead Sciences Inc | Anticorpos seletivos para células que apresentam egfr em alta densidade |
EP2670776B1 (en) | 2011-02-04 | 2018-11-21 | F. Hoffmann-La Roche AG | Fc VARIANTS AND METHODS FOR THEIR PRODUCTION |
US10689447B2 (en) | 2011-02-04 | 2020-06-23 | Genentech, Inc. | Fc variants and methods for their production |
US9353127B2 (en) | 2011-02-15 | 2016-05-31 | Immunogen, Inc. | Methods of preparation of conjugates |
JP6018621B2 (ja) | 2011-04-01 | 2016-11-02 | イミュノジェン, インコーポレイテッド | Folr1がん治療の有効性を増加させるための方法 |
MX368966B (es) | 2011-06-10 | 2019-10-23 | Mersana Therapeutics Inc | Conjugados de proteina-polimero-farmaco. |
US8815226B2 (en) | 2011-06-10 | 2014-08-26 | Mersana Therapeutics, Inc. | Protein-polymer-drug conjugates |
WO2013016714A1 (en) | 2011-07-28 | 2013-01-31 | Sea Lane Biotechnologies | Sur-binding proteins against erbb3 |
EP2758437B1 (en) | 2011-09-22 | 2020-06-03 | Amgen Inc. | Cd27l antigen binding proteins |
US9364551B2 (en) | 2011-09-29 | 2016-06-14 | Virginia Commonwealth University | Light-enabled drug delivery |
US20140314667A1 (en) | 2011-11-16 | 2014-10-23 | Amgen Inc. | Methods of treating epidermal growth factor deletion mutant viii related disorders |
JP2014533954A (ja) | 2011-11-21 | 2014-12-18 | イミュノジェン, インコーポレイテッド | Egfr抗体細胞傷害性薬物複合体による、egfr療法に耐性である腫瘍の治療方法 |
KR20140100571A (ko) | 2011-12-08 | 2014-08-14 | 바이오테스트 아게 | Cd138을 타겟팅하는 면역접합체의 용도 |
EP2793940B1 (en) | 2011-12-22 | 2018-11-14 | i2 Pharmaceuticals, Inc. | Surrogate binding proteins |
WO2013092983A2 (en) * | 2011-12-23 | 2013-06-27 | Innate Pharma | Enzymatic conjugation of polypeptides |
WO2013109994A1 (en) | 2012-01-20 | 2013-07-25 | Sea Lane Biotechnologies, Llc | Surrobody cojugates |
KR20140127854A (ko) | 2012-02-10 | 2014-11-04 | 제넨테크, 인크. | 단일-쇄 항체 및 다른 이종다량체 |
AR090549A1 (es) | 2012-03-30 | 2014-11-19 | Genentech Inc | Anticuerpos anti-lgr5 e inmunoconjugados |
WO2013150623A1 (ja) * | 2012-04-04 | 2013-10-10 | 株式会社ペルセウスプロテオミクス | 抗cdh3(p-カドヘリン)抗体の薬剤コンジュゲート |
US10130714B2 (en) | 2012-04-14 | 2018-11-20 | Academia Sinica | Enhanced anti-influenza agents conjugated with anti-inflammatory activity |
MX2014013041A (es) * | 2012-04-27 | 2015-03-19 | Cytomx Therapeutics Inc | Anticuerpos activables que se ligan al receptor del factor de crecimiento epidermico y metodos de uso de los mismos. |
EP2844300B1 (en) | 2012-05-01 | 2018-10-17 | Genentech, Inc. | Anti-pmel17 antibodies and immunoconjugates |
NZ630870A (en) | 2012-05-15 | 2016-10-28 | Seattle Genetics Inc | Self-stabilizing linker conjugates |
US9884127B2 (en) | 2012-05-15 | 2018-02-06 | Concortis Biosystems, Corp. | Drug-conjugates, conjugation methods, and uses thereof |
US9504756B2 (en) | 2012-05-15 | 2016-11-29 | Seattle Genetics, Inc. | Self-stabilizing linker conjugates |
CN104540519B (zh) | 2012-05-21 | 2018-06-01 | 基因泰克公司 | 抗Ly6E抗体和免疫缀合物及使用方法 |
WO2014001325A1 (en) | 2012-06-27 | 2014-01-03 | F. Hoffmann-La Roche Ag | Method for making antibody fc-region conjugates comprising at least one binding entity that specifically binds to a target and uses thereof |
EP2867253B1 (en) | 2012-06-27 | 2016-09-14 | F. Hoffmann-La Roche AG | Method for selection and production of tailor-made highly selective and multi-specific targeting entities containing at least two different binding entities and uses thereof |
JP2015528818A (ja) | 2012-08-02 | 2015-10-01 | ジェネンテック, インコーポレイテッド | 抗etbr抗体およびイムノコンジュゲート |
JP2015529656A (ja) | 2012-08-02 | 2015-10-08 | ジェネンテック, インコーポレイテッド | 抗etbr抗体および免疫複合体 |
JP6302909B2 (ja) | 2012-08-18 | 2018-03-28 | アカデミア シニカAcademia Sinica | シアリダーゼの同定および画像化のための細胞透過性プローブ |
PT2900676T (pt) | 2012-09-26 | 2019-03-29 | Immunogen Inc | Método melhorado para a acilação de maitansinol |
US9636413B2 (en) | 2012-11-15 | 2017-05-02 | Endocyte, Inc. | Conjugates for treating diseases caused by PSMA expressing cells |
AU2012395148B2 (en) | 2012-11-24 | 2016-10-27 | Hangzhou Dac Biotech Co., Ltd. | Hydrophilic linkers and their uses for conjugation of drugs to cell binding molecules |
CN103333246B (zh) * | 2012-12-21 | 2015-09-16 | 百奥泰生物科技(广州)有限公司 | 一种抗egfr受体的肿瘤生长抑制剂及其制备方法和用途 |
US9999680B2 (en) | 2013-02-28 | 2018-06-19 | Immunogen, Inc. | Conjugates comprising cell-binding agents and maytansinoids as cytotoxic agents |
WO2014134486A2 (en) | 2013-02-28 | 2014-09-04 | Immunogen, Inc. | Conjugates comprising cell-binding agents and cytotoxic agents |
SG11201507037XA (en) | 2013-03-14 | 2015-10-29 | Genentech Inc | Anti-b7-h4 antibodies and immunoconjugates |
US9562099B2 (en) | 2013-03-14 | 2017-02-07 | Genentech, Inc. | Anti-B7-H4 antibodies and immunoconjugates |
CA2902872A1 (en) | 2013-03-15 | 2014-09-18 | Regeneron Pharmaceuticals, Inc. | Biologically active molecules, conjugates thereof, and therapeutic uses |
US10611824B2 (en) | 2013-03-15 | 2020-04-07 | Innate Pharma | Solid phase TGase-mediated conjugation of antibodies |
EP2976362B1 (en) | 2013-03-19 | 2019-10-23 | Beijing Shenogen Pharma Group Ltd. | Antibodies and methods for treating estrogen receptor-associated diseases |
WO2014194030A2 (en) | 2013-05-31 | 2014-12-04 | Immunogen, Inc. | Conjugates comprising cell-binding agents and cytotoxic agents |
BR112015030514A2 (pt) * | 2013-06-04 | 2017-08-29 | Cytomx Therapeutics Inc | Composições e métodos para conjugação de anticorpos ativáveis |
WO2014210397A1 (en) | 2013-06-26 | 2014-12-31 | Academia Sinica | Rm2 antigens and use thereof |
EP3013347B1 (en) | 2013-06-27 | 2019-12-11 | Academia Sinica | Glycan conjugates and use thereof |
JP6462673B2 (ja) | 2013-07-05 | 2019-01-30 | フォーメーション バイオロジックス インコーポレイテッド | Egfr抗体コンジュゲート |
RU2560699C2 (ru) * | 2013-08-02 | 2015-08-20 | федеральное государственное автономное образовательное учреждение высшего профессионального образования "Национальный исследовательский ядерный университет МИФИ" (НИЯУ МИФИ) | Способ создания наноразмерной диагностической метки на основе конъюгатов наночастиц и однодоменных антител |
US9545451B2 (en) | 2013-08-21 | 2017-01-17 | Regeneron Pharmaceuticals, Inc. | Anti-PRLR antibodies and methods for killing PRLR-expressing cells |
TWI641620B (zh) | 2013-08-21 | 2018-11-21 | 再生元醫藥公司 | 抗-prlr抗體及其用途 |
JP6608823B2 (ja) | 2013-08-26 | 2019-11-20 | レゲネロン ファーマシューティカルス,インコーポレーテッド | マクロライドジアステレオマーを含む医薬組成物、その合成方法、及び治療上の使用 |
SG11201600645SA (en) | 2013-09-05 | 2016-03-30 | Jackson Lab | Compositions for rna-chromatin interaction analysis and uses thereof |
EP3041484B1 (en) | 2013-09-06 | 2021-03-03 | Academia Sinica | Human inkt cell activation using glycolipids with altered glycosyl groups |
WO2015042108A1 (en) | 2013-09-17 | 2015-03-26 | Genentech, Inc. | Methods of using anti-lgr5 antibodies |
PT3055332T (pt) | 2013-10-08 | 2019-12-09 | Immunogen Inc | Regimes de dosagem de imunoconjugados anti-folr1 |
EP3054991B1 (en) | 2013-10-11 | 2019-04-03 | Mersana Therapeutics, Inc. | Protein-polymer-drug conjugates |
CN115068626A (zh) | 2013-10-11 | 2022-09-20 | 阿萨纳生物科技有限责任公司 | 蛋白-聚合物-药物缀合物 |
RU2016134258A (ru) | 2013-10-15 | 2018-02-28 | Сорренто Терапьютикс Инк. | Конъюгат лекарственного средства с направляющей молекулой и двумя различными лекарственными средствами |
EA201690780A1 (ru) | 2013-10-15 | 2016-08-31 | Сиэтл Дженетикс, Инк. | Пегилированные лекарственные средства-линкеры для улучшенной фармакокинетики конъюгатов лиганд-лекарственное средство |
EP3456700A1 (en) | 2013-10-18 | 2019-03-20 | Deutsches Krebsforschungszentrum | Labeled inhibitors of prostate specific membrane antigen (psma), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer |
AR098126A1 (es) | 2013-10-21 | 2016-05-04 | Genentech Inc | Anticuerpos anti-ly6e (locus e del complejo del antígeno 6 linfocítico), inmunoconjugados y métodos para usarlos |
US9540440B2 (en) | 2013-10-30 | 2017-01-10 | Cytomx Therapeutics, Inc. | Activatable antibodies that bind epidermal growth factor receptor and methods of use thereof |
AU2014357292B2 (en) | 2013-11-27 | 2020-06-25 | Zymeworks Bc Inc. | Bispecific antigen-binding constructs targeting HER2 |
WO2015089283A1 (en) | 2013-12-11 | 2015-06-18 | Cytomx Therapeutics, Inc. | Antibodies that bind activatable antibodies and methods of use thereof |
TWI541022B (zh) | 2013-12-18 | 2016-07-11 | 應克隆公司 | 針對纖維母細胞生長因子受體-3(fgfr3)之化合物及治療方法 |
TWI777502B (zh) | 2013-12-19 | 2022-09-11 | 美商西雅圖遺傳學公司 | 與標的-藥物結合物併用之亞甲基胺基甲酸酯連接物 |
JPWO2015108203A1 (ja) | 2014-01-15 | 2017-03-23 | 株式会社オーダーメードメディカルリサーチ | 抗slc6a6抗体を用いたがん治療用医薬組成物 |
US9943606B2 (en) | 2014-01-15 | 2018-04-17 | Rutgers, The State University Of New Jersey | Dendritic polypeptide-based nanocarriers for the delivery of therapeutic agents |
US10150818B2 (en) | 2014-01-16 | 2018-12-11 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
CA2937123A1 (en) | 2014-01-16 | 2015-07-23 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
CA2938450C (en) | 2014-02-11 | 2023-10-17 | Seattle Genetics, Inc. | Selective reduction of proteins |
FI3122757T3 (fi) | 2014-02-28 | 2023-10-10 | Hangzhou Dac Biotech Co Ltd | Varautuneita linkkereitä ja niiden konjugointikäyttötapoja |
EP3129767B1 (en) | 2014-03-27 | 2021-09-01 | Academia Sinica | Reactive labelling compounds and uses thereof |
BR122021009041B1 (pt) | 2014-05-06 | 2022-11-29 | Genentech, Inc | Métodos para a preparação de uma proteína heteromultimérica |
KR20170003720A (ko) | 2014-05-27 | 2017-01-09 | 아카데미아 시니카 | 항-cd20 글리코항체 및 이의 용도 |
KR20170005142A (ko) | 2014-05-27 | 2017-01-11 | 아카데미아 시니카 | 증진된 항체 효능을 위한 범용 당형태에 관한 조성물 및 방법 |
US10118969B2 (en) | 2014-05-27 | 2018-11-06 | Academia Sinica | Compositions and methods relating to universal glycoforms for enhanced antibody efficacy |
EP3149037A4 (en) | 2014-05-27 | 2018-01-10 | Academia Sinica | Anti-her2 glycoantibodies and uses thereof |
TWI732738B (zh) | 2014-05-28 | 2021-07-11 | 中央研究院 | 抗TNF-α醣抗體及其用途 |
US10973920B2 (en) | 2014-06-30 | 2021-04-13 | Glykos Finland Oy | Saccharide derivative of a toxic payload and antibody conjugates thereof |
WO2016008112A1 (en) | 2014-07-16 | 2016-01-21 | Medshine Discovery Inc. | Linkers and application towards adc thereof |
US9982045B2 (en) | 2014-08-12 | 2018-05-29 | Novartis Ag | Anti-CDH6 antibody drug conjugates |
KR20240011258A (ko) | 2014-09-02 | 2024-01-25 | 이뮤노젠 아이엔씨 | 항체 약물 컨쥬게이트 조성물의 제형화 방법 |
SG11201701455SA (en) | 2014-09-03 | 2017-03-30 | Immunogen Inc | Cytotoxic benzodiazepine derivatives |
WO2016036804A1 (en) | 2014-09-03 | 2016-03-10 | Immunogen, Inc. | Cytotoxic benzodiazepine derivatives |
KR102422375B1 (ko) | 2014-09-08 | 2022-07-18 | 아카데미아 시니카 | 당지질을 사용한 인간 iNKT 세포 활성화 |
CN113827737A (zh) | 2014-09-11 | 2021-12-24 | 西雅图基因公司 | 含叔胺药物物质的靶向递送 |
US10059768B2 (en) | 2014-09-12 | 2018-08-28 | Genentech, Inc. | Anti-B7-H4 antibodies and immunoconjugates |
WO2016075670A1 (en) | 2014-11-14 | 2016-05-19 | Novartis Ag | Antibody drug conjugates |
ES2764111T3 (es) | 2014-12-03 | 2020-06-02 | Hoffmann La Roche | Anticuerpos multiespecíficos |
AU2015358367B2 (en) | 2014-12-04 | 2020-07-02 | Celgene Corporation | Biomolecule conjugates |
US10188759B2 (en) | 2015-01-07 | 2019-01-29 | Endocyte, Inc. | Conjugates for imaging |
US10495645B2 (en) | 2015-01-16 | 2019-12-03 | Academia Sinica | Cancer markers and methods of use thereof |
US9975965B2 (en) | 2015-01-16 | 2018-05-22 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
WO2016118191A1 (en) | 2015-01-24 | 2016-07-28 | Academia Sinica | Novel glycan conjugates and methods of use thereof |
CN107849090A (zh) | 2015-01-28 | 2018-03-27 | 索伦托医疗有限公司 | 抗体药物偶联物 |
EP3286227A2 (en) | 2015-04-24 | 2018-02-28 | F. Hoffmann-La Roche AG | Multispecific antigen-binding proteins |
TW201711702A (zh) | 2015-06-04 | 2017-04-01 | 應克隆公司 | 使用針對纖維母細胞生長因子受體3(fgfr3)之化合物的療法 |
WO2016203432A1 (en) | 2015-06-17 | 2016-12-22 | Novartis Ag | Antibody drug conjugates |
CA2988806A1 (en) | 2015-06-29 | 2017-01-05 | Immunogen, Inc. | Conjugates of cysteine engineered antibodies |
WO2015151081A2 (en) | 2015-07-12 | 2015-10-08 | Suzhou M-Conj Biotech Co., Ltd | Bridge linkers for conjugation of a cell-binding molecule |
US9839687B2 (en) | 2015-07-15 | 2017-12-12 | Suzhou M-Conj Biotech Co., Ltd. | Acetylenedicarboxyl linkers and their uses in specific conjugation of a cell-binding molecule |
US9873708B2 (en) | 2015-07-21 | 2018-01-23 | Immunogen, Inc. | Methods of preparing cytotoxic benzodiazepine derivatives |
US10509035B2 (en) | 2015-08-07 | 2019-12-17 | Gamamabs Pharma Sa | Antibodies, antibody drug conjugates and methods of use |
CN114814055A (zh) * | 2015-09-08 | 2022-07-29 | 沃特世科技公司 | 用于分析抗体-药物缀合物的多维色谱方法 |
CN108601828B (zh) | 2015-09-17 | 2023-04-28 | 伊缪诺金公司 | 包含抗folr1免疫缀合物的治疗组合 |
CN116396393A (zh) | 2015-10-08 | 2023-07-07 | 酵活英属哥伦比亚省公司 | 包含κ和λ轻链的抗原结合多肽构建体及其用途 |
PT3380525T (pt) | 2015-11-25 | 2024-02-05 | Immunogen Inc | Formulações farmacêuticas e métodos que as utilizam |
TWI814699B (zh) | 2015-12-04 | 2023-09-11 | 美商思進公司 | 四級胺化妥布賴森(tubulysin)化合物之結合物 |
US11793880B2 (en) | 2015-12-04 | 2023-10-24 | Seagen Inc. | Conjugates of quaternized tubulysin compounds |
MY198605A (en) | 2016-01-25 | 2023-09-08 | Regeneron Pharma | Maytansinoid derivatives conjugates thereof, and methods of use |
CA3019952A1 (en) | 2016-02-04 | 2017-08-10 | Curis, Inc. | Mutant smoothened and methods of using the same |
US10336784B2 (en) | 2016-03-08 | 2019-07-02 | Academia Sinica | Methods for modular synthesis of N-glycans and arrays thereof |
WO2017165851A1 (en) | 2016-03-25 | 2017-09-28 | Seattle Genetics, Inc. | Process for the preparation of pegylated drug-linkers and intermediates thereof |
KR20230149857A (ko) | 2016-07-07 | 2023-10-27 | 더 보드 어브 트러스티스 어브 더 리랜드 스탠포드 주니어 유니버시티 | 항체-애쥬번트 접합체 |
SG11201900699QA (en) | 2016-08-09 | 2019-02-27 | Seattle Genetics Inc | Drug conjugates with self-stabilizing linkers having improved physiochemical properties |
US9950070B2 (en) * | 2016-08-16 | 2018-04-24 | Korea University Research And Business Foundation | HER2 aptamer-anticancer drug complex for cancer cell chemotherapy |
US10538592B2 (en) | 2016-08-22 | 2020-01-21 | Cho Pharma, Inc. | Antibodies, binding fragments, and methods of use |
US11638762B2 (en) | 2016-10-18 | 2023-05-02 | Seagen Inc. | Targeted delivery of nicotinamide adenine dinucleotide salvage pathway inhibitors |
CN110177805B (zh) | 2016-10-19 | 2024-04-02 | 英温拉公司 | 抗体构建体 |
KR102459468B1 (ko) | 2016-11-14 | 2022-10-26 | 항저우 디에이씨 바이오테크 씨오, 엘티디 | 결합 링커, 그러한 결합 링커를 함유하는 세포 결합 분자-약물 결합체, 링커를 갖는 그러한 결합체의 제조 및 사용 |
EP3544983A2 (en) | 2016-11-23 | 2019-10-02 | Immunogen, Inc. | Selective sulfonation of benzodiazepine derivatives |
US10925971B2 (en) | 2016-11-29 | 2021-02-23 | Regeneron Pharmaceuticals, Inc. | Methods of treating PRLR positive breast cancer |
JP7244987B2 (ja) | 2016-12-14 | 2023-03-23 | シージェン インコーポレイテッド | 多剤抗体薬物コンジュゲート |
WO2018115485A1 (en) | 2016-12-22 | 2018-06-28 | Pierfrancesco Tassone | A monoclonal antibody targeting a unique sialoglycosilated cancer-associated epitope of cd43 |
WO2018119196A1 (en) | 2016-12-23 | 2018-06-28 | Immunogen, Inc. | Immunoconjugates targeting adam9 and methods of use thereof |
WO2018129029A1 (en) | 2017-01-04 | 2018-07-12 | Immunogen, Inc. | Met antibodies and immunoconjugates and uses thereof |
JOP20190187A1 (ar) | 2017-02-03 | 2019-08-01 | Novartis Ag | مترافقات عقار جسم مضاد لـ ccr7 |
IL298414A (en) | 2017-02-28 | 2023-01-01 | Immunogen Inc | History of methanosinoids with peptide linkers and their conjugates |
IL269398B1 (en) | 2017-03-24 | 2024-01-01 | Seagen Inc | A process for the preparation of glucuronide-drug binders and their intermediates |
WO2018185618A1 (en) | 2017-04-03 | 2018-10-11 | Novartis Ag | Anti-cdh6 antibody drug conjugates and anti-gitr antibody combinations and methods of treatment |
TW201839001A (zh) | 2017-04-20 | 2018-11-01 | 美商伊繆諾金公司 | 細胞毒性苯并二氮平衍生物及其綴合物 |
US20180311375A1 (en) * | 2017-04-27 | 2018-11-01 | Cadila Healthcare Limited | Process of preparing antibody-drug conjugate |
CA3060206A1 (en) | 2017-04-27 | 2018-11-01 | Seattle Genetics, Inc. | Quaternized nicotinamide adenine dinucleotide salvage pathway inhibitor conjugates |
CA3074111A1 (en) | 2017-08-28 | 2019-03-07 | Angiex, Inc. | Anti-tm4sf1 antibodies and methods of using same |
EP3732178A1 (en) | 2017-12-28 | 2020-11-04 | ImmunoGen, Inc. | Benzodiazepine derivatives |
WO2019150985A1 (ja) * | 2018-01-31 | 2019-08-08 | 国立大学法人東京大学 | 抗体薬物複合体及びそれを含む医薬組成物 |
MX2020010729A (es) | 2018-04-13 | 2021-03-09 | Genentech Inc | Formulaciones de inmunoconjugado anti-cd79b estables. |
EP3802580A1 (en) | 2018-06-05 | 2021-04-14 | King's College London | Btnl3/8 targeting constructs for delivery of payloads to the gastrointestinal system |
BR112020025346A2 (pt) | 2018-06-26 | 2021-05-25 | Immunogen, Inc. | imunoconjugados que alvejam adam9 e métodos de uso dos mesmos |
WO2020014306A1 (en) | 2018-07-10 | 2020-01-16 | Immunogen, Inc. | Met antibodies and immunoconjugates and uses thereof |
TW202029980A (zh) | 2018-10-26 | 2020-08-16 | 美商免疫遺傳股份有限公司 | E p C A M 抗體、可活化抗體及免疫偶聯物以及其用途 |
AU2020241686A1 (en) | 2019-03-15 | 2021-11-04 | Bolt Biotherapeutics, Inc. | Immunoconjugates targeting HER2 |
WO2020187998A1 (en) | 2019-03-19 | 2020-09-24 | Fundació Privada Institut D'investigació Oncològica De Vall Hebron | Combination therapy with omomyc and an antibody binding pd-1 or ctla-4 for the treatment of cancer |
WO2020191342A1 (en) | 2019-03-20 | 2020-09-24 | The Regents Of The University Of California | Claudin-6 antibodies and drug conjugates |
JP2022529583A (ja) | 2019-03-29 | 2022-06-23 | イミュノジェン・インコーポレーテッド | 異常細胞増殖を阻害するまたは増殖性疾患を治療するための細胞毒性ビス-ベンゾジアゼピン誘導体及び細胞結合剤とのその複合体 |
EP3958977B1 (en) | 2019-04-26 | 2023-09-13 | ImmunoGen, Inc. | Camptothecin derivatives |
EP4036149A4 (en) | 2019-09-26 | 2023-10-25 | NOF Corporation | HETEROBIFUNCTIONAL MONODISPERSPERED POLYETHYLENE GLYCOL WITH PEPTIDE LINKER |
WO2021136223A1 (en) | 2019-12-31 | 2021-07-08 | Beijing Ql Biopharmaceutical Co., Ltd. | Fusion proteins of glp-1 and gdf15 and conjugates thereof |
CN113728013B (zh) | 2020-01-11 | 2022-06-14 | 北京质肽生物医药科技有限公司 | Glp-1和fgf21的融合蛋白的缀合物 |
CN115551552A (zh) | 2020-02-25 | 2022-12-30 | 祐方有限公司 | 喜树碱衍生物及其缀合物 |
BR112022020332A2 (pt) | 2020-04-10 | 2022-12-13 | Seagen Inc | Composto conjugado anticorpo-droga, composição, método de tratamento de câncer e de um distúrbio autoimune |
US20230181756A1 (en) | 2020-04-30 | 2023-06-15 | Novartis Ag | Ccr7 antibody drug conjugates for treating cancer |
EP4178624A2 (en) | 2020-07-07 | 2023-05-17 | Bionecure Therapeutics, Inc. | Maytansinoids as adc payloads and their use for the treatment of cancer |
US20220378929A1 (en) | 2021-02-25 | 2022-12-01 | MediBoston Limted | Anti-her2 antibody-drug conjugates and uses thereof |
US20240108744A1 (en) | 2022-07-27 | 2024-04-04 | Mediboston Limited | Auristatin derivatives and conjugates thereof |
Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4256746A (en) | 1978-11-14 | 1981-03-17 | Takeda Chemical Industries | Dechloromaytansinoids, their pharmaceutical compositions and method of use |
US4294757A (en) | 1979-01-31 | 1981-10-13 | Takeda Chemical Industries, Ltd | 20-O-Acylmaytansinoids |
US4307016A (en) | 1978-03-24 | 1981-12-22 | Takeda Chemical Industries, Ltd. | Demethyl maytansinoids |
US4313946A (en) | 1981-01-27 | 1982-02-02 | The United States Of America As Represented By The Secretary Of Agriculture | Chemotherapeutically active maytansinoids from Trewia nudiflora |
US4315929A (en) | 1981-01-27 | 1982-02-16 | The United States Of America As Represented By The Secretary Of Agriculture | Method of controlling the European corn borer with trewiasine |
US4322348A (en) | 1979-06-05 | 1982-03-30 | Takeda Chemical Industries, Ltd. | Maytansinoids |
US4331598A (en) | 1979-09-19 | 1982-05-25 | Takeda Chemical Industries, Ltd. | Maytansinoids |
US4362663A (en) | 1979-09-21 | 1982-12-07 | Takeda Chemical Industries, Ltd. | Maytansinoid compound |
US4364866A (en) | 1979-09-21 | 1982-12-21 | Takeda Chemical Industries, Ltd. | Maytansinoids |
US4371533A (en) | 1980-10-08 | 1983-02-01 | Takeda Chemical Industries, Ltd. | 4,5-Deoxymaytansinoids, their use and pharmaceutical compositions thereof |
US4424219A (en) | 1981-05-20 | 1984-01-03 | Takeda Chemical Industries, Ltd. | 9-Thiomaytansinoids and their pharmaceutical compositions and use |
US4450254A (en) | 1980-11-03 | 1984-05-22 | Standard Oil Company | Impact improvement of high nitrile resins |
US5208020A (en) | 1989-10-25 | 1993-05-04 | Immunogen Inc. | Cytotoxic agents comprising maytansinoids and their therapeutic use |
US6333410B1 (en) | 2000-08-18 | 2001-12-25 | Immunogen, Inc. | Process for the preparation and purification of thiol-containing maytansinoids |
US6441163B1 (en) | 2001-05-31 | 2002-08-27 | Immunogen, Inc. | Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents |
Family Cites Families (138)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3896111A (en) | 1973-02-20 | 1975-07-22 | Research Corp | Ansa macrolides |
US4151042A (en) | 1977-03-31 | 1979-04-24 | Takeda Chemical Industries, Ltd. | Method for producing maytansinol and its derivatives |
GB1603640A (en) | 1977-07-20 | 1981-11-25 | Gist Brocades Nv | Enzyme particles |
US4137230A (en) | 1977-11-14 | 1979-01-30 | Takeda Chemical Industries, Ltd. | Method for the production of maytansinoids |
US4265814A (en) | 1978-03-24 | 1981-05-05 | Takeda Chemical Industries | Matansinol 3-n-hexadecanoate |
JPS5562090A (en) | 1978-10-27 | 1980-05-10 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS55164687A (en) | 1979-06-11 | 1980-12-22 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS5566585A (en) | 1978-11-14 | 1980-05-20 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS55164685A (en) | 1979-06-08 | 1980-12-22 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS55164686A (en) | 1979-06-11 | 1980-12-22 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
US4309428A (en) | 1979-07-30 | 1982-01-05 | Takeda Chemical Industries, Ltd. | Maytansinoids |
US4867973A (en) | 1984-08-31 | 1989-09-19 | Cytogen Corporation | Antibody-therapeutic agent conjugates |
JPS58167592A (ja) | 1982-03-26 | 1983-10-03 | Takeda Chem Ind Ltd | 新規メイタンシノイド化合物 |
LU86212A1 (fr) | 1985-12-16 | 1987-07-24 | Omnichem Sa | Nouveaux conjugues de la vinblastine et de ses derives,procede pour leur preparation et compositions pharmaceutiques les contenant |
US7838216B1 (en) | 1986-03-05 | 2010-11-23 | The United States Of America, As Represented By The Department Of Health And Human Services | Human gene related to but distinct from EGF receptor gene |
US5395924A (en) | 1986-03-20 | 1995-03-07 | Dana-Farber Cancer Institute, Inc. | Blocked lectins; methods and affinity support for making the same using affinity ligands; and method of killing selected cell populations having reduced non-selective cytotoxicity |
US4968603A (en) | 1986-12-31 | 1990-11-06 | The Regents Of The University Of California | Determination of status in neoplastic disease |
US4981979A (en) | 1987-09-10 | 1991-01-01 | Neorx Corporation | Immunoconjugates joined by thioether bonds having reduced toxicity and improved selectivity |
JPS6484959A (en) | 1987-09-25 | 1989-03-30 | Nec Corp | System for connecting test line |
US5824311A (en) | 1987-11-30 | 1998-10-20 | Trustees Of The University Of Pennsylvania | Treatment of tumors with monoclonal antibodies against oncogene antigens |
WO1989006692A1 (en) | 1988-01-12 | 1989-07-27 | Genentech, Inc. | Method of treating tumor cells by inhibiting growth factor receptor function |
US5720937A (en) | 1988-01-12 | 1998-02-24 | Genentech, Inc. | In vivo tumor detection assay |
US5217713A (en) | 1988-12-27 | 1993-06-08 | Takeda Chemical Industries, Ltd. | Cytotoxic bispecific monoclonal antibody, its production and use |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5705157A (en) | 1989-07-27 | 1998-01-06 | The Trustees Of The University Of Pennsylvania | Methods of treating cancerous cells with anti-receptor antibodies |
US5154924A (en) | 1989-09-07 | 1992-10-13 | Alkermes, Inc. | Transferrin receptor specific antibody-neuropharmaceutical agent conjugates |
CA2026147C (en) | 1989-10-25 | 2006-02-07 | Ravi J. Chari | Cytotoxic agents comprising maytansinoids and their therapeutic use |
US5183884A (en) | 1989-12-01 | 1993-02-02 | United States Of America | Dna segment encoding a gene for a receptor related to the epidermal growth factor receptor |
FR2656555B1 (fr) * | 1989-12-29 | 1994-10-28 | Serimer | Systeme mecanique de guidage automatique d'une ou plusieurs torches d'une unite de soudage a l'arc. |
GB9015198D0 (en) | 1990-07-10 | 1990-08-29 | Brien Caroline J O | Binding substance |
IL101943A0 (en) | 1991-05-24 | 1992-12-30 | Genentech Inc | Structure,production and use of heregulin |
EP0590058B1 (en) | 1991-06-14 | 2003-11-26 | Genentech, Inc. | HUMANIZED Heregulin ANTIBODy |
WO1994004679A1 (en) | 1991-06-14 | 1994-03-03 | Genentech, Inc. | Method for making humanized antibodies |
SE9102074D0 (sv) | 1991-07-03 | 1991-07-03 | Kabi Pharmacia Ab | Tomour antigen specific antibody |
CA2096417C (en) | 1991-08-22 | 2000-10-10 | Sarah S. Bacus | Methods and compositions for cancer therapy and for prognosticating responses to cancer therapy |
JP3951062B2 (ja) | 1991-09-19 | 2007-08-01 | ジェネンテック・インコーポレーテッド | 少なくとも遊離のチオールとして存在するシステインを有する抗体フラグメントの大腸菌での発現、2官能性F(ab’)2抗体の産生のための使用 |
WO1994000136A1 (en) | 1992-06-30 | 1994-01-06 | Oncologix, Inc. | A COMBINATION OF ANTI-erbB-2 MONOCLONAL ANTIBODIES AND METHOD OF USING |
US6022541A (en) | 1991-10-18 | 2000-02-08 | Beth Israel Deaconess Medical Center | Immunological preparation for concurrent specific binding to spatially exposed regions of vascular permeability factor bound in-vivo to a tumor associated blood vessel |
WO1993011236A1 (en) | 1991-12-02 | 1993-06-10 | Medical Research Council | Production of anti-self antibodies from antibody segment repertoires and displayed on phage |
ATE419355T1 (de) | 1992-02-06 | 2009-01-15 | Novartis Vaccines & Diagnostic | Marker für krebs und biosynthetisches bindeprotein dafür |
EP0563475B1 (en) | 1992-03-25 | 2000-05-31 | Immunogen Inc | Cell binding agent conjugates of derivatives of CC-1065 |
WO1993021319A1 (en) | 1992-04-08 | 1993-10-28 | Cetus Oncology Corporation | HUMANIZED C-erbB-2 SPECIFIC ANTIBODIES |
US7754211B2 (en) | 1992-04-10 | 2010-07-13 | Research Development Foundation | Immunotoxins directed against c-erbB-2(HER-2/neu) related surface antigens |
JP2861631B2 (ja) | 1992-05-06 | 1999-02-24 | 日本電気株式会社 | Fsk受信機 |
US6217869B1 (en) | 1992-06-09 | 2001-04-17 | Neorx Corporation | Pretargeting methods and compounds |
US5639641A (en) * | 1992-09-09 | 1997-06-17 | Immunogen Inc. | Resurfacing of rodent antibodies |
AU6527894A (en) | 1993-03-30 | 1994-10-24 | Trustees Of The University Of Pennsylvania, The | Prevention of tumors with monoclonal antibodies against (neu) |
CA2205356A1 (en) | 1994-11-21 | 1996-05-30 | Peter Edward Urwin | Modified proteinase inhibitors |
US5679648A (en) * | 1994-11-30 | 1997-10-21 | The University Hospital | Methods for the treatment and prevention of fungal infections by administration of 3'-deoxypurine nucleosides |
US5837234A (en) | 1995-06-07 | 1998-11-17 | Cytotherapeutics, Inc. | Bioartificial organ containing cells encapsulated in a permselective polyether suflfone membrane |
ATE483733T1 (de) | 1995-06-14 | 2010-10-15 | Univ California | Hochaffine humane antikörper gegen tumorantigene |
US5614692A (en) | 1995-06-30 | 1997-03-25 | Tracor Aerospace, Inc. | Shaped-charge device with progressive inward collapsing jet |
RU2497500C2 (ru) | 1995-07-27 | 2013-11-10 | Джинентех, Инк | Стабильная изотоническая лиофилизированная протеиновая композиция |
US5783186A (en) | 1995-12-05 | 1998-07-21 | Amgen Inc. | Antibody-induced apoptosis |
US5919815A (en) | 1996-05-22 | 1999-07-06 | Neuromedica, Inc. | Taxane compounds and compositions |
US5968517A (en) | 1996-05-23 | 1999-10-19 | Duncan; Kelvin Winston | Process for extraction of proanthocyanidins from botanical material |
US5922845A (en) | 1996-07-11 | 1999-07-13 | Medarex, Inc. | Therapeutic multispecific compounds comprised of anti-Fcα receptor antibodies |
WO1998008506A1 (en) | 1996-08-30 | 1998-03-05 | Eli Lilly And Company | Pharmaceutical compounds |
JPH1084959A (ja) * | 1996-09-06 | 1998-04-07 | Nobuyoshi Shimizu | 細胞表面レセプターに対するモノクローナル抗体ならびにそのフラグメントの結合体ならびに複合体、それらの製法ならびに細胞への嵌入方法および使用方法 |
CN1116299C (zh) * | 1996-09-20 | 2003-07-30 | 明治制果株式会社 | 头孢地托伦新戊酰氧甲酯晶体及其生产方法 |
AU4982097A (en) | 1996-10-18 | 1998-05-15 | Board Of Regents, The University Of Texas System | Anti-erbb2 antibodies |
WO1998020020A2 (en) | 1996-11-06 | 1998-05-14 | Sequenom, Inc. | High density immobilization of nucleic acids |
EP0944652B1 (en) | 1996-12-12 | 2003-10-15 | E.I. Du Pont De Nemours And Company | Improved packaging composition |
US7122636B1 (en) | 1997-02-21 | 2006-10-17 | Genentech, Inc. | Antibody fragment-polymer conjugates and uses of same |
US8173127B2 (en) | 1997-04-09 | 2012-05-08 | Intellect Neurosciences, Inc. | Specific antibodies to amyloid beta peptide, pharmaceutical compositions and methods of use thereof |
WO1999006587A2 (en) | 1997-08-01 | 1999-02-11 | Morphosys Ag | Novel method and phage for the identification of nucleic acid sequences encoding members of a multimeric (poly)peptide complex |
US20030060612A1 (en) | 1997-10-28 | 2003-03-27 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
US6387657B1 (en) | 1997-10-29 | 2002-05-14 | Genentech, Inc. | WISP polypeptides and nucleic acids encoding same |
ZA9811162B (en) | 1997-12-12 | 2000-06-07 | Genentech Inc | Treatment with anti-ERBB2 antibodies. |
US6914130B2 (en) | 1998-06-17 | 2005-07-05 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
US6747055B1 (en) * | 1998-07-17 | 2004-06-08 | The United States Of America As Represented By The Department Of Health And Human Services | Water-soluble drugs and methods for their production |
AU5963699A (en) | 1998-10-02 | 2000-04-26 | Mcmaster University | Spliced form of (erb)b-2/neu oncogene |
AU770952B2 (en) | 1999-03-01 | 2004-03-11 | Genentech Inc. | Antibodies for cancer therapy and diagnosis |
DE60042968D1 (de) | 1999-04-01 | 2009-10-29 | Hana Biosciences Inc | Zusammensetzungen und methoden zur behandlung lymphoma |
CN101073668A (zh) | 1999-04-28 | 2007-11-21 | 德克萨斯大学董事会 | 用于通过选择性抑制vegf来治疗癌症的组合物和方法 |
EP1176981B1 (en) | 1999-05-07 | 2005-11-30 | Genentech, Inc. | Treatment of autoimmune diseases with antagonists which bind to b cell surface markers |
AU4809299A (en) | 1999-05-12 | 2000-12-05 | Array Ab | Direct printing device with cleaning unit |
JP5623681B2 (ja) | 1999-05-14 | 2014-11-12 | ジェネンテック, インコーポレイテッド | 抗−ErbB2抗体による治療 |
CA2370466C (en) | 1999-06-25 | 2011-02-08 | Sharon Erickson | Methods of treatment using anti-erbb antibody-maytansinoid conjugates |
US6656730B1 (en) | 1999-06-15 | 2003-12-02 | Isis Pharmaceuticals, Inc. | Oligonucleotides conjugated to protein-binding drugs |
US20040013667A1 (en) * | 1999-06-25 | 2004-01-22 | Genentech, Inc. | Treatment with anti-ErbB2 antibodies |
MXPA01013395A (es) | 1999-06-25 | 2003-09-04 | Genentech Inc | Tratamiento de cancer de prostata con anticuerpos anti-erbb2. |
EP1189641B1 (en) | 1999-06-25 | 2009-07-29 | Genentech, Inc. | HUMANIZED ANTI-ErbB2 ANTIBODIES AND TREATMENT WITH ANTI-ErbB2 ANTIBODIES |
US20030086924A1 (en) * | 1999-06-25 | 2003-05-08 | Genentech, Inc. | Treatment with anti-ErbB2 antibodies |
US7041292B1 (en) | 1999-06-25 | 2006-05-09 | Genentech, Inc. | Treating prostate cancer with anti-ErbB2 antibodies |
US6949245B1 (en) | 1999-06-25 | 2005-09-27 | Genentech, Inc. | Humanized anti-ErbB2 antibodies and treatment with anti-ErbB2 antibodies |
US6362342B1 (en) | 1999-06-29 | 2002-03-26 | Lion Bioscience Ag | Triazole compounds and methods of making same |
JP2003528805A (ja) | 1999-07-12 | 2003-09-30 | ジェネンテック・インコーポレーテッド | Cd20に結合するアンタゴニストを用いた異種抗原に対する免疫応答のブロッキング |
US6531131B1 (en) | 1999-08-10 | 2003-03-11 | The United States Of America As Represented By The Department Of Health And Human Services | Conjugate vaccine for Neisseria meningitidis |
US6635677B2 (en) | 1999-08-13 | 2003-10-21 | Case Western Reserve University | Methoxyamine combinations in the treatment of cancer |
SI1210115T1 (sl) | 1999-08-27 | 2009-12-31 | Genentech Inc | Doziranja za zdravljenje s protitelesi proti ErbB2 |
US7030231B1 (en) | 1999-09-30 | 2006-04-18 | Catalyst Biosciences, Inc. | Membrane type serine protease 1 (MT-SP1) and uses thereof |
US7303749B1 (en) * | 1999-10-01 | 2007-12-04 | Immunogen Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
EP2289549A3 (en) | 1999-10-01 | 2011-06-15 | Immunogen, Inc. | Immunoconjugates for treating cancer |
BE1012928A6 (nl) | 1999-10-07 | 2001-06-05 | Hoeberigs Jean Marie Mathieu | Cilinderoven voor verwarming van frites met hete lucht. |
ES2309012T3 (es) | 1999-10-29 | 2008-12-16 | Genentech, Inc. | Composiciones del anticuerpo anti-psca y a sus procedimientos contra celulas cancerigenas que expresen psca. |
US6824780B1 (en) | 1999-10-29 | 2004-11-30 | Genentech, Inc. | Anti-tumor antibody compositions and methods of use |
DE60032633T2 (de) | 1999-11-24 | 2007-10-04 | Immunogen Inc., Cambridge | Zytotoxische mittel, die taxane enthalten und ihre therapeutische anwendung |
KR100796079B1 (ko) * | 2000-02-11 | 2008-01-21 | 일라이 릴리 앤드 캄파니 | A82846 글리코펩티드 동족체의 선택적 n-아실화 |
AU783679B2 (en) | 2000-02-24 | 2005-11-24 | Genentech Inc. | Caspase activated prodrugs therapy |
US6632979B2 (en) | 2000-03-16 | 2003-10-14 | Genentech, Inc. | Rodent HER2 tumor model |
US7097840B2 (en) | 2000-03-16 | 2006-08-29 | Genentech, Inc. | Methods of treatment using anti-ErbB antibody-maytansinoid conjugates |
JP2003531588A (ja) | 2000-04-11 | 2003-10-28 | ジェネンテック・インコーポレーテッド | 多価抗体とその用途 |
WO2002013843A2 (en) | 2000-08-17 | 2002-02-21 | University Of British Columbia | Chemotherapeutic agents conjugated to p97 and their methods of use in treating neurological tumours |
US6596503B1 (en) | 2000-08-18 | 2003-07-22 | East Carolina University | Monoclonal antibody DS6, tumor-associated antigen CA6, and methods of use thereof |
CA2420140A1 (en) | 2000-08-24 | 2002-02-28 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
ATE457318T1 (de) | 2000-12-28 | 2010-02-15 | Kyowa Hakko Kirin Co Ltd | Gegen das menschliche bst2 antigen gerichteter monoklonaler antikörper |
CA2633595A1 (en) | 2001-06-20 | 2003-01-03 | Genentech, Inc. | Antibodies against tumor-associated antigenic target (tat) polypeptides |
US20080085283A1 (en) | 2001-09-05 | 2008-04-10 | Levinson Arthur D | Methods for the identification of polypeptide antigens associated with disorders involving aberrant cell proliferation and compositions useful for the treatment of such disorders |
US20040235068A1 (en) | 2001-09-05 | 2004-11-25 | Levinson Arthur D. | Methods for the identification of polypeptide antigens associated with disorders involving aberrant cell proliferation and compositions useful for the treatment of such disorders |
AU2002332838B2 (en) * | 2001-09-05 | 2007-08-02 | Genentech, Inc. | Methods for the identification of polypeptide antigens associated with disorders involving aberrant cell proliferation and compositions useful for the treatment of such disorders |
US20030109682A1 (en) * | 2001-09-07 | 2003-06-12 | Daniel Santi | Maytansines and maytansine conjugates |
ATE486092T1 (de) | 2001-09-18 | 2010-11-15 | Genentech Inc | Zusammensetzungen und verfahren für die diagnose von tumoren |
US20050238650A1 (en) | 2002-04-17 | 2005-10-27 | Genentech, Inc. | Compositions and methods for the treatment of tumor of hematopoietic origin |
US6716821B2 (en) * | 2001-12-21 | 2004-04-06 | Immunogen Inc. | Cytotoxic agents bearing a reactive polyethylene glycol moiety, cytotoxic conjugates comprising polyethylene glycol linking groups, and methods of making and using the same |
NZ533657A (en) | 2002-01-03 | 2008-01-31 | Smithkline Beecham Corp | Methods for the preparation of immunoconjugates, in particular maytansinoids conjugated to a monoclonal antibody |
US7094579B2 (en) | 2002-02-13 | 2006-08-22 | Xoma Technology Ltd. | Eukaryotic signal sequences for prokaryotic expression |
WO2005117986A2 (en) | 2004-06-01 | 2005-12-15 | Genentech, Inc. | Antibody drug conjugates and methods |
AU2003247762B2 (en) | 2002-07-03 | 2008-05-01 | Immunogen, Inc. | Antibodies to non-shed MUC1 and MUC16, and uses thereof |
ATE499116T1 (de) * | 2002-08-16 | 2011-03-15 | Immunogen Inc | Vernetzer mit hoher reaktivität und löslichkeit und ihre verwendung bei der herstellung von konjugaten für die gezielte abgabe von kleinmolekularen arzneimitteln |
EP1578371A4 (en) | 2002-08-19 | 2009-05-20 | Genentech Inc | COMPOSITIONS AND METHODS FOR DIAGNOSING AND TREATING TUMORS |
EA009285B1 (ru) * | 2003-05-14 | 2007-12-28 | Иммуноджен, Инк. | Композиция конъюгированного лекарственного средства |
US8088387B2 (en) | 2003-10-10 | 2012-01-03 | Immunogen Inc. | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates |
US7276497B2 (en) * | 2003-05-20 | 2007-10-02 | Immunogen Inc. | Cytotoxic agents comprising new maytansinoids |
MXPA06000830A (es) | 2003-07-21 | 2006-04-18 | Immunogen Inc | Un conjugado citotoxico ca6 antigeno-especifico y metodos para utilizar el mismo. |
US7754441B2 (en) | 2003-11-17 | 2010-07-13 | Genentech, Inc. | Compositions and methods for the treatment of tumor of hematopoietic origin |
JP3991983B2 (ja) | 2003-12-19 | 2007-10-17 | 日産自動車株式会社 | 車両の駆動制御装置 |
JP4658967B2 (ja) | 2003-12-24 | 2011-03-23 | ジェネンテック, インコーポレイテッド | 造血系起源の腫瘍の治療のための組成物と方法 |
US7375078B2 (en) | 2004-02-23 | 2008-05-20 | Genentech, Inc. | Heterocyclic self-immolative linkers and conjugates |
DK1791565T3 (en) | 2004-09-23 | 2016-08-01 | Genentech Inc | Cysteingensplejsede antibodies and conjugates |
JP2006316040A (ja) | 2005-05-13 | 2006-11-24 | Genentech Inc | Herceptin(登録商標)補助療法 |
DK2135881T3 (da) | 2005-06-20 | 2011-12-05 | Genentech Inc | Antistoffer, som binder til det tumor-associerede antigen TAT10772, til diagnose og behandling af tumor |
US7195520B1 (en) | 2006-07-18 | 2007-03-27 | Chung-Chuan Huang | Connector for antenna |
KR20210131473A (ko) | 2008-03-18 | 2021-11-02 | 제넨테크, 인크. | 항-her2 항체-약물 접합체와 화학요법제의 병용물, 및 사용 방법 |
MY157165A (en) * | 2008-04-30 | 2016-05-13 | Immunogen Inc | Cross-linkers and their uses |
US20110165155A1 (en) | 2009-12-04 | 2011-07-07 | Genentech, Inc. | Methods of treating metastatic breast cancer with trastuzumab-mcc-dm1 |
CA2792618C (en) | 2010-03-12 | 2018-09-25 | Immunogen, Inc. | Cd37-binding molecules and immunoconjugates thereof |
BR112013014316A2 (pt) | 2010-12-09 | 2016-09-27 | Genentech Inc | tratamento de câncer her2-positivo com paclitaxel e trastuzumabe-mcc-dm1 |
-
2004
- 2004-10-08 US US10/960,602 patent/US8088387B2/en active Active
- 2004-10-12 NZ NZ583844A patent/NZ583844A/en unknown
- 2004-10-12 EP EP12196827.5A patent/EP2596804A3/en not_active Withdrawn
- 2004-10-12 EP EP12196813.5A patent/EP2596803A3/en active Pending
- 2004-10-12 PL PL04793896T patent/PL1689846T3/pl unknown
- 2004-10-12 KR KR1020137020144A patent/KR101476082B1/ko active IP Right Grant
- 2004-10-12 KR KR1020067006874A patent/KR20060130552A/ko not_active Application Discontinuation
- 2004-10-12 EP EP12196817.6A patent/EP2612682A3/en not_active Withdrawn
- 2004-10-12 WO PCT/US2004/030917 patent/WO2005037992A2/en active Application Filing
- 2004-10-12 AU AU2004282491A patent/AU2004282491C1/en active Active
- 2004-10-12 EP EP04793896A patent/EP1689846B1/en active Active
- 2004-10-12 ES ES04793896T patent/ES2404304T3/es active Active
- 2004-10-12 NZ NZ545195A patent/NZ545195A/en unknown
- 2004-10-12 KR KR1020137023561A patent/KR101573124B1/ko active IP Right Grant
- 2004-10-12 CN CN201810464381.7A patent/CN108578710B/zh active Active
- 2004-10-12 KR KR1020127004142A patent/KR101343676B1/ko active IP Right Grant
- 2004-10-12 CN CN201710333830.XA patent/CN107198778A/zh not_active Withdrawn
- 2004-10-12 DK DK04793896.4T patent/DK1689846T3/da active
- 2004-10-12 PT PT47938964T patent/PT1689846E/pt unknown
- 2004-10-12 CA CA3139478A patent/CA3139478A1/en active Pending
- 2004-10-12 SI SI200432024T patent/SI1689846T1/sl unknown
- 2004-10-12 BR BRPI0415448A patent/BRPI0415448A8/pt not_active Application Discontinuation
- 2004-10-12 EA EA200600752A patent/EA010508B1/ru active Protection Beyond IP Right Term
- 2004-10-12 JP JP2006533951A patent/JP2007520450A/ja active Pending
- 2004-10-12 CA CA2542128A patent/CA2542128C/en active Active
- 2004-10-12 CN CN201310118580XA patent/CN103223174A/zh active Pending
-
2006
- 2006-02-09 IL IL173625A patent/IL173625A/en active IP Right Grant
- 2006-03-28 EC EC2006006461A patent/ECSP066461A/es unknown
- 2006-04-21 NO NO20061772A patent/NO337458B1/no active Protection Beyond IP Right Term
-
2007
- 2007-10-29 US US11/927,217 patent/US8163888B2/en active Active
- 2007-10-29 US US11/927,251 patent/US7989598B2/en active Active
- 2007-10-29 US US11/927,235 patent/US8563509B2/en active Active
- 2007-10-29 US US11/927,314 patent/US8198417B2/en active Active
-
2008
- 2008-02-27 HK HK18104043.9A patent/HK1244452A1/zh unknown
-
2010
- 2010-08-12 AU AU2010212291A patent/AU2010212291C1/en active Active
-
2011
- 2011-07-04 JP JP2011148625A patent/JP5718745B2/ja active Active
- 2011-07-08 US US13/178,728 patent/US8685920B2/en active Active
- 2011-08-22 IL IL214788A patent/IL214788A0/en active IP Right Grant
-
2012
- 2012-05-11 US US13/469,550 patent/US20120226025A1/en not_active Abandoned
-
2013
- 2013-05-08 CY CY20131100372T patent/CY1113984T1/el unknown
- 2013-05-09 HR HRP20130412TT patent/HRP20130412T1/hr unknown
- 2013-12-13 HU HUS1300075C patent/HUS1300075I1/hu unknown
- 2013-12-16 LU LU92336C patent/LU92336I2/fr unknown
- 2013-12-18 BE BE2013C075C patent/BE2013C075I2/fr unknown
-
2014
- 2014-01-16 CY CY2014002C patent/CY2014002I1/el unknown
- 2014-02-04 US US14/172,360 patent/US20140154804A1/en not_active Abandoned
- 2014-04-07 JP JP2014078553A patent/JP5926759B2/ja active Active
- 2014-10-21 IL IL235253A patent/IL235253B/en active IP Right Grant
-
2016
- 2016-01-26 NO NO2016001C patent/NO2016001I1/no not_active IP Right Cessation
- 2016-02-08 JP JP2016021695A patent/JP2016135786A/ja active Pending
- 2016-07-05 IL IL246605A patent/IL246605A/en active IP Right Grant
-
2017
- 2017-01-23 US US15/413,153 patent/US10844135B2/en active Active
- 2017-06-12 JP JP2017114877A patent/JP2017200934A/ja not_active Withdrawn
-
2018
- 2018-10-02 JP JP2018187555A patent/JP2019011363A/ja active Pending
-
2019
- 2019-03-04 JP JP2019038151A patent/JP2019142864A/ja active Pending
-
2020
- 2020-08-05 JP JP2020132965A patent/JP2020189854A/ja not_active Withdrawn
- 2020-10-07 US US17/064,981 patent/US20210261683A1/en not_active Abandoned
-
2022
- 2022-02-18 JP JP2022023780A patent/JP2022068295A/ja not_active Withdrawn
Patent Citations (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4307016A (en) | 1978-03-24 | 1981-12-22 | Takeda Chemical Industries, Ltd. | Demethyl maytansinoids |
US4361650A (en) | 1978-03-24 | 1982-11-30 | Takeda Chemical Industries, Ltd. | Fermentation process of preparing demethyl maytansinoids |
US4256746A (en) | 1978-11-14 | 1981-03-17 | Takeda Chemical Industries | Dechloromaytansinoids, their pharmaceutical compositions and method of use |
US4294757A (en) | 1979-01-31 | 1981-10-13 | Takeda Chemical Industries, Ltd | 20-O-Acylmaytansinoids |
US4322348A (en) | 1979-06-05 | 1982-03-30 | Takeda Chemical Industries, Ltd. | Maytansinoids |
US4331598A (en) | 1979-09-19 | 1982-05-25 | Takeda Chemical Industries, Ltd. | Maytansinoids |
US4364866A (en) | 1979-09-21 | 1982-12-21 | Takeda Chemical Industries, Ltd. | Maytansinoids |
US4362663A (en) | 1979-09-21 | 1982-12-07 | Takeda Chemical Industries, Ltd. | Maytansinoid compound |
US4371533A (en) | 1980-10-08 | 1983-02-01 | Takeda Chemical Industries, Ltd. | 4,5-Deoxymaytansinoids, their use and pharmaceutical compositions thereof |
US4450254A (en) | 1980-11-03 | 1984-05-22 | Standard Oil Company | Impact improvement of high nitrile resins |
US4315929A (en) | 1981-01-27 | 1982-02-16 | The United States Of America As Represented By The Secretary Of Agriculture | Method of controlling the European corn borer with trewiasine |
US4313946A (en) | 1981-01-27 | 1982-02-02 | The United States Of America As Represented By The Secretary Of Agriculture | Chemotherapeutically active maytansinoids from Trewia nudiflora |
US4424219A (en) | 1981-05-20 | 1984-01-03 | Takeda Chemical Industries, Ltd. | 9-Thiomaytansinoids and their pharmaceutical compositions and use |
US5208020A (en) | 1989-10-25 | 1993-05-04 | Immunogen Inc. | Cytotoxic agents comprising maytansinoids and their therapeutic use |
US5416064A (en) | 1989-10-25 | 1995-05-16 | Immunogen, Inc. | Cytotoxic agents comprising maytansinoids and their therapeutic use |
US6333410B1 (en) | 2000-08-18 | 2001-12-25 | Immunogen, Inc. | Process for the preparation and purification of thiol-containing maytansinoids |
US6441163B1 (en) | 2001-05-31 | 2002-08-27 | Immunogen, Inc. | Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents |
Non-Patent Citations (7)
Title |
---|
CHARI ET AL., CANCER RES., vol. 52, 1992, pages 127 - 133 |
GOLDMACHER ET AL., J. CELL BIOL., vol. 102, 1986, pages 1312 - 1319 |
GOLDMACHER ET AL., J. IMMUNOL., vol. 135, 1985, pages 3648 - 3651 |
HASLAM, TETRAHEDRON, vol. 36, 1980, pages 2400 - 2433 |
NISONOFF ET AL., ARCH. BIOCHEM. BIOPHYS., vol. 89, 1960, pages 230 - 244 |
PARHAM, J. IMMUNOL., vol. 131, 1983, pages 2895 - 2902 |
SPRING ET AL., J. IMMUNOL., vol. 113, 1974, pages 470 - 478 |
Cited By (163)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9085630B2 (en) | 2002-11-15 | 2015-07-21 | Genentech, Inc. | Compositions and methods for the treatment of tumor of hematopoietic origin |
KR101343676B1 (ko) | 2003-10-10 | 2013-12-20 | 이뮤노젠 아이엔씨 | 메이탠시노이드 화합물 |
US10844135B2 (en) | 2003-10-10 | 2020-11-24 | Immunogen, Inc. | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates and methods of making said |
EP2286844A2 (en) | 2004-06-01 | 2011-02-23 | Genentech, Inc. | Antibody-drug conjugates and methods |
WO2005117986A2 (en) * | 2004-06-01 | 2005-12-15 | Genentech, Inc. | Antibody drug conjugates and methods |
EP2286844A3 (en) * | 2004-06-01 | 2012-08-22 | Genentech, Inc. | Antibody-drug conjugates and methods |
AU2005249490B2 (en) * | 2004-06-01 | 2010-07-29 | Genentech, Inc. | Antibody drug conjugates and methods |
WO2005117986A3 (en) * | 2004-06-01 | 2006-06-15 | Genentech Inc | Antibody drug conjugates and methods |
RU2404810C9 (ru) * | 2004-06-01 | 2015-06-20 | Дженентек, Инк. | Конъюгаты антитело-лекарственное средство и способы |
JP2008501029A (ja) * | 2004-06-01 | 2008-01-17 | ジェネンテック・インコーポレーテッド | 抗体−薬物結合体および方法 |
US8142784B2 (en) | 2004-06-01 | 2012-03-27 | Genentech, Inc. | Antibody-drug conjugates and methods |
US8652479B2 (en) | 2004-06-01 | 2014-02-18 | Genentech, Inc. | Antibody-drug conjugates and methods |
EP3088004A1 (en) | 2004-09-23 | 2016-11-02 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
WO2006086733A3 (en) * | 2005-02-11 | 2007-06-07 | Immunogen Inc | Process for preparing maytansinoid antibody conjugates |
US8933205B2 (en) | 2005-08-24 | 2015-01-13 | Immunogen, Inc. | Process for preparing purified drug conjugates |
JP2014196307A (ja) * | 2005-08-24 | 2014-10-16 | イムノゲン インコーポレーティッド | メイタンシノイド(maytansinoid)抗体複合体の調製方法 |
JP2013014604A (ja) * | 2005-08-24 | 2013-01-24 | Immunogen Inc | メイタンシノイド(maytansinoid)抗体複合体の調製方法 |
US11471536B2 (en) | 2005-08-24 | 2022-10-18 | Immunogen, Inc. | Process for preparing purified drug conjugates |
US9789204B2 (en) | 2005-08-24 | 2017-10-17 | Immunogen, Inc. | Process for preparing purified drug conjugates |
US8383122B2 (en) | 2005-08-24 | 2013-02-26 | Immunogen, Inc. | Process for preparing purified drug conjugates |
US7811572B2 (en) | 2005-08-24 | 2010-10-12 | Immunogen, Inc. | Process for preparing purified drug conjugates |
JP2009506032A (ja) * | 2005-08-24 | 2009-02-12 | イムノゲン インコーポレーティッド | メイタンシノイド(maytansinoid)抗体複合体の調製方法 |
US11033628B1 (en) | 2005-10-14 | 2021-06-15 | Phigenix, Inc. | Targeting PAX2 for the treatment of breast cancer |
EP1942944A2 (en) * | 2005-10-31 | 2008-07-16 | Genentech, Inc. | Macrocyclic depsipeptide antibody-drug conjugates and methods |
EP2446904A2 (en) | 2006-05-30 | 2012-05-02 | Genentech, Inc. | Anti-CD22 antibodies, their immunoconjugates and uses thereof |
US8524865B2 (en) | 2006-05-30 | 2013-09-03 | Genentech, Inc. | Antibodies and immunoconjugates and uses therefor |
US8968741B2 (en) | 2006-05-30 | 2015-03-03 | Genentech, Inc. | Anti-CD22 antibodies and immunoconjugates and methods of use |
US8226945B2 (en) | 2006-05-30 | 2012-07-24 | Genentech, Inc. | Antibodies and immunoconjugates and uses therefor |
US8394607B2 (en) | 2006-05-30 | 2013-03-12 | Genentech, Inc. | Anti-CD22 antibodies and immunoconjugates and methods of use |
EP2447282A2 (en) | 2006-05-30 | 2012-05-02 | Genentech, Inc. | Anti-CD22 Antibodies, their Immunoconjugates and uses thereof |
EP2845866A1 (en) | 2006-10-27 | 2015-03-11 | Genentech, Inc. | Antibodies and immunoconjugates and uses therefor |
US8691531B2 (en) | 2007-07-16 | 2014-04-08 | Genentech, Inc. | Anti-CD79B antibodies and immunoconjugates and methods of use |
US11866496B2 (en) | 2007-07-16 | 2024-01-09 | Genentech, Inc. | Humanized 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 |
US10494432B2 (en) | 2007-07-16 | 2019-12-03 | Genentech, Inc. | Anti-CD79B antibodies and immunoconjugates and methods of use |
EP2641618A2 (en) | 2007-07-16 | 2013-09-25 | Genentech, Inc. | Humanized anti-CD79B antibodies and immunoconjugates and methods of use |
US10981987B2 (en) | 2007-07-16 | 2021-04-20 | 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 |
US8088378B2 (en) | 2007-07-16 | 2012-01-03 | Genetech Inc. | Anti-CD79B antibodies and immunoconjugates and methods of use |
USRE48558E1 (en) | 2007-07-16 | 2021-05-18 | Genentech, Inc. | Anti-CD79B antibodies and immunoconjugates and methods of use |
US8545850B2 (en) | 2007-07-16 | 2013-10-01 | Genentech, Inc. | Anti-CD79B antibodies and immunoconjugates and methods of use |
US9845355B2 (en) | 2007-07-16 | 2017-12-19 | Genentech, Inc. | Humanized anti-CD79b antibodies and immunoconjugates and methods of use |
US8722857B2 (en) | 2008-01-31 | 2014-05-13 | Genentech, Inc. | Anti-CD79B antibodies and immunoconjugates and methods of use |
EP2657253A2 (en) | 2008-01-31 | 2013-10-30 | Genentech, Inc. | Anti-CD79b antibodies and immunoconjugates and methods of use |
US9896506B2 (en) | 2008-01-31 | 2018-02-20 | Genentech, Inc. | Anti-CD79B antibodies and immunoconjugates and methods of use |
US10544218B2 (en) | 2008-01-31 | 2020-01-28 | Genentech, Inc. | Anti-CD79B antibodies and immunoconjugates and methods of use |
US8663643B2 (en) | 2008-03-18 | 2014-03-04 | Genentech, Inc. | Combinations of an anti-HER2 antibody-drug conjugate and chemotherapeutic agents, and methods of use |
US20120226026A1 (en) * | 2008-04-30 | 2012-09-06 | Immunogen, Inc. | Potent conjugates and hydrophilic linkers |
US9150649B2 (en) | 2008-04-30 | 2015-10-06 | Immunogen, Inc. | Potent conjugates and hydrophilic linkers |
WO2010120561A1 (en) | 2009-04-01 | 2010-10-21 | Genentech, Inc. | Anti-fcrh5 antibodies and immunoconjugates and methods of use |
US10233257B2 (en) | 2009-06-03 | 2019-03-19 | Immunogen, Inc. | Methods for preparing antibody-drug conjugates |
US11498979B2 (en) | 2009-06-03 | 2022-11-15 | Immunogen, Inc. | Methods for preparing a purified maytansinoid conjugate in a solution |
US9771432B2 (en) | 2009-06-03 | 2017-09-26 | Immunogen, Inc. | Conjugation methods |
US10815309B2 (en) | 2009-06-03 | 2020-10-27 | Immunogen, Inc. | Methods for preparing antibody-drug conjugates |
US9376500B2 (en) | 2009-06-03 | 2016-06-28 | Immunogen, Inc. | Conjugation methods |
EP2896404A2 (en) | 2009-06-04 | 2015-07-22 | Novartis AG | Methods for identification of sites for IgG conjugation |
WO2010141902A2 (en) | 2009-06-04 | 2010-12-09 | Novartis Ag | METHODS FOR IDENTIFICATION OF SITES FOR IgG CONJUGATION |
EP3248619A2 (en) | 2009-06-04 | 2017-11-29 | Novartis AG | Methods for identification of sites for igg conjugation |
US9345661B2 (en) | 2009-07-31 | 2016-05-24 | Genentech, Inc. | Subcutaneous anti-HER2 antibody formulations and uses thereof |
US9968676B2 (en) | 2009-07-31 | 2018-05-15 | Genentech, Inc. | Subcutaneous anti-HER2 antibody formulations and uses thereof |
US10280227B2 (en) | 2009-09-11 | 2019-05-07 | Genentech, Inc. | Highly concentrated pharmaceutical formulations |
US10377831B2 (en) | 2009-09-11 | 2019-08-13 | Genentech, Inc. | Highly concentrated pharmaceutical formulations |
US10752696B2 (en) | 2009-09-11 | 2020-08-25 | Genentech, Inc. | Highly concentrated pharmaceutical formulations |
EP2486023A1 (en) * | 2009-10-06 | 2012-08-15 | ImmunoGen, Inc. | Potent conjugates and hydrophilic linkers |
EP2486023A4 (en) * | 2009-10-06 | 2014-05-07 | Immunogen Inc | EFFICIENT CONJUGATES AND HYDROPHILIC BINDER |
US10584181B2 (en) | 2009-12-04 | 2020-03-10 | Genentech, Inc. | Methods of making and using multispecific antibody panels and antibody analog panels |
EP3778917A2 (en) | 2009-12-04 | 2021-02-17 | F. Hoffmann-La Roche AG | Multispecific antibodies, antibody analogs, compositions, and methods |
US9346887B2 (en) | 2010-03-12 | 2016-05-24 | Immunogen, Inc. | CD37-binding molecules and immunoconjugates thereof |
US8765917B2 (en) | 2010-03-12 | 2014-07-01 | Immunogen, Inc. | CD37-binding molecules and immunoconjugates thereof |
US10202460B2 (en) | 2010-03-12 | 2019-02-12 | Debiopharm International, S.A. | CD37-binding molecules and immunoconjugates thereof |
US11466095B2 (en) | 2010-03-12 | 2022-10-11 | Debiopharm International S.A. | CD37-binding molecules and immunoconjugates thereof |
US8771966B2 (en) | 2010-06-03 | 2014-07-08 | Genentech, Inc. | Immuno-PET imaging of antibodies and immunoconjugates and uses therefor |
WO2011153346A1 (en) | 2010-06-03 | 2011-12-08 | Genentech, Inc. | Immuno-pet imaging of antibodies and immunoconjugates and uses therefor |
WO2011156328A1 (en) | 2010-06-08 | 2011-12-15 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
CN103328505A (zh) * | 2010-10-29 | 2013-09-25 | 伊缪诺金公司 | 非拮抗性egfr结合分子及其免疫偶联物 |
CN103328505B (zh) * | 2010-10-29 | 2015-12-02 | 伊缪诺金公司 | 非拮抗性egfr结合分子及其免疫偶联物 |
WO2012074757A1 (en) | 2010-11-17 | 2012-06-07 | Genentech, Inc. | Alaninyl maytansinol antibody conjugates |
US8795673B2 (en) | 2011-03-29 | 2014-08-05 | Immunogen, Inc. | Preparation of maytansinoid antibody conjugates by a one-step process |
US11090390B2 (en) | 2011-03-29 | 2021-08-17 | Immunogen, Inc. | Preparation of maytansinoid antibody conjugates by a one-step process |
WO2012135522A3 (en) * | 2011-03-29 | 2013-01-24 | Immunogen, Inc. | Process for manufacturing conjugates of improved homogeneity |
US9914748B2 (en) | 2011-03-29 | 2018-03-13 | Immunogen, Inc. | Preparation of maytansinoid antibody conjugates by a one-step process |
EA025786B1 (ru) * | 2011-03-29 | 2017-01-30 | Иммуноджен, Инк. | Способ производства конъюгатов с улучшенной гомогенностью |
US10435432B2 (en) | 2011-03-29 | 2019-10-08 | Immunogen, Inc. | Preparation of maytansinoid antibody conjugates by a one-step process |
US9428543B2 (en) | 2011-03-29 | 2016-08-30 | Immunogen, Inc. | Preparation of maytansinoid antibody conjugates by a one-step process |
US11744900B2 (en) | 2011-03-29 | 2023-09-05 | Immunogen, Inc. | Preparation of maytansinoid antibody conjugates by a one-step process |
US10556958B2 (en) | 2011-04-01 | 2020-02-11 | Debiopharm International, S.A. | CD37-binding molecules and immunoconjugates thereof |
US9447189B2 (en) | 2011-04-01 | 2016-09-20 | Immunogen, Inc. | CD37-binding molecules and immunoconjugates thereof |
WO2012154809A1 (en) | 2011-05-09 | 2012-11-15 | University Of Virginia Patent Foundation | Compositions and methods for treating cancer |
WO2012162561A2 (en) | 2011-05-24 | 2012-11-29 | Zyngenia, Inc. | Multivalent and monovalent multispecific complexes and their uses |
US10494423B2 (en) | 2011-06-21 | 2019-12-03 | Immunogen, Inc. | Maytansinoid derivatives with peptide linker and conjugates thereof |
WO2013063001A1 (en) | 2011-10-28 | 2013-05-02 | Genentech, Inc. | Therapeutic combinations and methods of treating melanoma |
WO2013130093A1 (en) | 2012-03-02 | 2013-09-06 | Genentech, Inc. | Biomarkers for treatment with anti-tubulin chemotherapeutic compounds |
US8883979B2 (en) | 2012-08-31 | 2014-11-11 | Bayer Healthcare Llc | Anti-prolactin receptor antibody formulations |
US10035817B2 (en) | 2012-10-04 | 2018-07-31 | Immunogen, Inc. | Method of purifying cell-binding agent-cytotoxic agent conjugates with a PVDF membrane |
US10918735B2 (en) | 2012-12-04 | 2021-02-16 | Massachusetts Institute Of Technology | Substituted pyrazino[1′,2′:1,5]pyrrolo[2,3-b]indole-1,4-diones for cancer treatment |
US8877706B2 (en) * | 2012-12-21 | 2014-11-04 | Bio-Thera Solutions Ltd., Co. | Maytansinoid derivatives |
WO2014160160A3 (en) * | 2013-03-13 | 2015-01-08 | Novartis Ag | Antibody drug conjugates and corresponding antibodies |
US9498532B2 (en) | 2013-03-13 | 2016-11-22 | Novartis Ag | Antibody drug conjugates |
EP2968600A4 (en) * | 2013-03-13 | 2017-03-08 | Petropoulos, Konstantin | Antibody drug conjugates |
US9415118B2 (en) | 2013-03-13 | 2016-08-16 | Novartis Ag | Antibody drug conjugates |
EP3514178A1 (en) * | 2013-03-15 | 2019-07-24 | Novartis AG | Antibody drug conjugates |
EA035253B1 (ru) * | 2013-03-15 | 2020-05-21 | Новартис Аг | Лекарственные конъюгаты антител |
WO2014150937A1 (en) * | 2013-03-15 | 2014-09-25 | Novartis Ag | Antibody drug conjugates |
US9789203B2 (en) | 2013-03-15 | 2017-10-17 | Novartis Ag | cKIT antibody drug conjugates |
US10117953B2 (en) | 2013-03-15 | 2018-11-06 | Novartis Ag | Antibody drug conjugates |
WO2014182970A1 (en) | 2013-05-08 | 2014-11-13 | Zymeworks Inc. | Bispecific her2 and her3 antigen binding constructs |
US11224663B2 (en) | 2013-05-31 | 2022-01-18 | Pharma Mar, S.A. | Antibody drug conjugates |
US10071170B2 (en) | 2013-06-24 | 2018-09-11 | Ablbio | Antibody-drug conjugate having improved stability and use thereof |
WO2014208987A1 (ko) | 2013-06-24 | 2014-12-31 | 한화케미칼 주식회사 | 안정성이 개선된 항체-약물 결합체 및 이의 용도 |
EP3699200A1 (en) | 2013-07-15 | 2020-08-26 | Cell Signaling Technology, Inc. | Anti-mucin 1 binding agents and uses thereof |
WO2015009740A2 (en) | 2013-07-15 | 2015-01-22 | Cell Signaling Technology, Inc. | Anti-mucin 1 binding agents and uses thereof |
WO2015073721A1 (en) | 2013-11-13 | 2015-05-21 | Zymeworks Inc. | Monovalent antigen binding constructs targeting egfr and/or her2 and uses thereof |
EP3521292A1 (en) | 2014-01-27 | 2019-08-07 | Pfizer Inc | Bifunctional cytotoxic agents |
WO2015110935A1 (en) | 2014-01-27 | 2015-07-30 | Pfizer Inc. | Bifunctional cytotoxic agents |
US10391182B2 (en) | 2014-01-27 | 2019-08-27 | Pfizer Inc. | Bifunctional cytotoxic agents |
US10086085B2 (en) | 2014-01-27 | 2018-10-02 | Pfizer Inc. | Bifunctional cytotoxic agents |
US10562977B2 (en) | 2014-01-29 | 2020-02-18 | Shanghai Hengrui Pharmaceutical Co., Ltd. | Ligand-cytotoxic drug conjugate, preparation method thereof, and uses thereof |
WO2015113476A1 (zh) | 2014-01-29 | 2015-08-06 | 上海恒瑞医药有限公司 | 配体-细胞毒性药物偶联物、其制备方法及其应用 |
EP3164420A4 (en) * | 2014-06-30 | 2018-05-23 | Tarveda Therapeutics, Inc. | Targeted conjugates and particles and formulations thereof |
US10624967B2 (en) | 2014-06-30 | 2020-04-21 | Tarveda Therapeutics, Inc. | Targeted conjugates and particles and formulations thereof |
US10322191B2 (en) | 2014-06-30 | 2019-06-18 | Tarveda Therapeutics, Inc. | Targeted conjugates and particles and formulations thereof |
EP3160518A4 (en) * | 2014-06-30 | 2018-05-23 | Tarveda Therapeutics, Inc. | Targeted conjugates and particles and formulations thereof |
US11458206B2 (en) | 2014-06-30 | 2022-10-04 | Tva (Abc), Llc | Targeted conjugates and particles and formulations thereof |
WO2016040856A2 (en) | 2014-09-12 | 2016-03-17 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
US11000510B2 (en) | 2014-09-23 | 2021-05-11 | Genentech, Inc. | Methods of using anti-CD79b immunoconjugates |
US10835616B2 (en) | 2014-10-14 | 2020-11-17 | Polytherics Limited | Process for the conjugation of a peptide or protein with a reagent comprising a leaving group including a portion of PEG |
US10870706B2 (en) | 2015-03-20 | 2020-12-22 | Pfizer Inc. | Bifunctional cytotoxic agents containing the CTI pharmacophore |
US11365263B2 (en) | 2015-03-20 | 2022-06-21 | Pfizer Inc. | Bifunctional cytotoxic agents containing the CTI pharmacophore |
WO2016151432A1 (en) | 2015-03-20 | 2016-09-29 | Pfizer Inc. | Bifunctional cytotoxic agents containing the cti pharmacophore |
US11395796B2 (en) | 2015-06-08 | 2022-07-26 | Debiopharm International, S.A. | Anti-CD37 immunoconjugate and anti-CD20 antibody combinations |
US10449258B2 (en) | 2015-06-09 | 2019-10-22 | Xdcexplorer (Shanghai) Co., Ltd. | Antibody drug conjugate, intermediate, preparation method, pharmaceutical composition and uses thereof |
EP3308801A4 (en) * | 2015-06-09 | 2019-02-27 | XDCExplorer (Shanghai) Co., Ltd. | ANTIBODY-MEDICINAL CONJUGATE, INTERMEDIATE, PREPARATION METHOD, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF |
EP3316863A4 (en) * | 2015-06-30 | 2019-02-13 | Tarveda Therapeutics, Inc. | DIRECTED CONJUGATES AND PARTICLES AND FORMULATIONS THEREOF |
US11104740B2 (en) | 2015-08-28 | 2021-08-31 | Debiopharm International, S.A. | Antibodies and assays for detection of CD37 |
US11160871B2 (en) | 2015-10-28 | 2021-11-02 | Tarveda Therapeutics, Inc. | SSTR-targeted conjugates and particles and formulations thereof |
US11779663B2 (en) | 2016-02-04 | 2023-10-10 | Hangzhou Dac Biotech Co., Ltd. | Specific conjugation linkers, specific immunoconjugates thereof, methods of making and uses such conjugates thereof |
US10548881B2 (en) | 2016-02-23 | 2020-02-04 | Tarveda Therapeutics, Inc. | HSP90 targeted conjugates and particles and formulations thereof |
US11510910B2 (en) | 2016-02-23 | 2022-11-29 | Tva (Abc), Llc | HSP90 targeted conjugates and particles and formulations thereof |
US10918627B2 (en) | 2016-05-11 | 2021-02-16 | Massachusetts Institute Of Technology | Convergent and enantioselective total synthesis of Communesin analogs |
US11278629B2 (en) | 2016-11-02 | 2022-03-22 | Debiopharm International, S.A. | Methods for improving anti-CD37 immunoconjugate therapy |
US10538535B2 (en) | 2017-04-27 | 2020-01-21 | Pharma Mar, S.A. | Antitumoral compounds |
US11332480B2 (en) | 2017-04-27 | 2022-05-17 | Pharma Mar, S.A. | Antitumoral compounds |
US11339180B2 (en) | 2017-04-27 | 2022-05-24 | Pharma Mar, S.A. | Antitumoral compounds |
US11713325B2 (en) | 2017-04-27 | 2023-08-01 | Pharma Mar, S.A. | Antitumoral compounds |
US11932650B2 (en) | 2017-05-11 | 2024-03-19 | Massachusetts Institute Of Technology | Potent agelastatin derivatives as modulators for cancer invasion and metastasis |
US10640508B2 (en) | 2017-10-13 | 2020-05-05 | Massachusetts Institute Of Technology | Diazene directed modular synthesis of compounds with quaternary carbon centers |
KR20210038904A (ko) | 2018-07-25 | 2021-04-08 | 다이이찌 산쿄 가부시키가이샤 | 항체-약물 콘쥬게이트의 효과적인 제조 방법 |
WO2020022363A1 (ja) | 2018-07-25 | 2020-01-30 | 第一三共株式会社 | 抗体-薬物コンジュゲートの効果的な製造方法 |
WO2020063676A1 (zh) | 2018-09-26 | 2020-04-02 | 江苏恒瑞医药股份有限公司 | 依喜替康类似物的配体-药物偶联物及其制备方法和应用 |
WO2020216947A1 (en) | 2019-04-24 | 2020-10-29 | Heidelberg Pharma Research Gmbh | Amatoxin antibody-drug conjugates and uses thereof |
US11535634B2 (en) | 2019-06-05 | 2022-12-27 | Massachusetts Institute Of Technology | Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof |
US11555019B2 (en) | 2019-07-10 | 2023-01-17 | Cybrexa 3, Inc. | Peptide conjugates of microtubule-targeting agents as therapeutics |
US11634508B2 (en) | 2019-07-10 | 2023-04-25 | Cybrexa 2, Inc. | Peptide conjugates of cytotoxins as therapeutics |
WO2021052402A1 (zh) | 2019-09-18 | 2021-03-25 | 四川百利药业有限责任公司 | 一种喜树碱衍生物及其偶联物 |
WO2021148003A1 (zh) | 2020-01-22 | 2021-07-29 | 上海森辉医药有限公司 | 艾日布林衍生物的药物偶联物、其制备方法及其在医药上的应用 |
CN111195353A (zh) * | 2020-03-19 | 2020-05-26 | 烟台迈百瑞国际生物医药有限公司 | 一种美登素类抗体药物偶联物及其应用 |
WO2021190581A1 (zh) | 2020-03-25 | 2021-09-30 | 江苏恒瑞医药股份有限公司 | 一种含抗体药物偶联物的药物组合物及其用途 |
WO2021190602A1 (zh) | 2020-03-25 | 2021-09-30 | 江苏恒瑞医药股份有限公司 | 一种抗体药物偶联物的制备方法 |
WO2022217022A1 (en) | 2021-04-10 | 2022-10-13 | Profoundbio Us Co. | Folr1 binding agents, conjugates thereof and methods of using the same |
WO2022226317A1 (en) | 2021-04-23 | 2022-10-27 | Profoundbio Us Co. | Anti-cd70 antibodies, conjugates thereof and methods of using the same |
WO2023092099A1 (en) | 2021-11-19 | 2023-05-25 | Ardeagen Corporation | Gpc3 binding agents, conjugates thereof and methods of using the same |
WO2023169896A1 (en) | 2022-03-09 | 2023-09-14 | Astrazeneca Ab | BINDING MOLECULES AGAINST FRα |
WO2023170216A1 (en) | 2022-03-11 | 2023-09-14 | Astrazeneca Ab | A SCORING METHOD FOR AN ANTI-FRα ANTIBODY-DRUG CONJUGATE THERAPY |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20210261683A1 (en) | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates and methods of making said conjugates | |
ZA200601182B (en) | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200480026459.3 Country of ref document: CN |
|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2006/01182 Country of ref document: ZA Ref document number: 545195 Country of ref document: NZ Ref document number: 173625 Country of ref document: IL Ref document number: 200601182 Country of ref document: ZA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004282491 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2006/002949 Country of ref document: MX |
|
ENP | Entry into the national phase |
Ref document number: 2004282491 Country of ref document: AU Date of ref document: 20041012 Kind code of ref document: A |
|
WWP | Wipo information: published in national office |
Ref document number: 2004282491 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 06027260 Country of ref document: CO |
|
WWE | Wipo information: entry into national phase |
Ref document number: CR2006-008319 Country of ref document: CR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2542128 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020067006874 Country of ref document: KR Ref document number: 2006533951 Country of ref document: JP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004793896 Country of ref document: EP Ref document number: 200600752 Country of ref document: EA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1470/KOLNP/2006 Country of ref document: IN |
|
WWP | Wipo information: published in national office |
Ref document number: 2004793896 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: PI0415448 Country of ref document: BR |
|
WWP | Wipo information: published in national office |
Ref document number: 1020067006874 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 214788 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 246605 Country of ref document: IL |