Human antibodies and antibody-drug conjugates against cd74

Abstract

Isolated human monoclonal antibodies which bind to human CD74 and related antibody-drug conjugates are disclosed. Pharmaceutical compositions comprising the antibodies or antibody-drug conjugates, and therapeutic and diagnostic methods for using the antibodies and/or antibody-drug conjugates, are also disclosed.

1 - 56 . (canceled) 
     
     
         57 . A method of cancer prophylaxis comprising administering to a subject in need thereof an antibody which binds to the same epitope on variants 1 and 2 of human CD74 as at least one antibody selected from:
 (a) an antibody comprising a VH region comprising the sequence of SEQ ID NO:19 and a VL region comprising the sequence of SEQ ID NO:26 [011];   (b) an antibody comprising a VH region comprising the sequence of SEQ ID NO:7 and a VL region comprising the sequence of SEQ ID NO:23 [005];   (c) an antibody comprising a VH region comprising the sequence of SEQ ID NO:11 and a VL region comprising the sequence of SEQ ID NO:26 [006]; and   (d) an antibody comprising a VH region comprising the sequence of SEQ ID NO:15 and a VL region comprising the sequence of SEQ ID NO:26 [008].   
     
     
         58 . The method of  claim 57 , wherein the method reduces the risk for developing cancer. 
     
     
         59 . The method of  claim 57 , wherein the method reduces the risk for recurrence of a cancer. 
     
     
         60 . The method of  claim 57 , wherein the antibody is administered in association with surgical removal of a CD74-expressing primary tumor. 
     
     
         61 . The method of  claim 57 , wherein the antibody is administered in association with radiotherapy of a CD74-expressing primary tumor. 
     
     
         62 . The method of  claim 57 , wherein the antibody
 (a) binds to the extracellular domain of CD74 variant 1 with an EC 50  of less than about 500 ng/mL;   (b) binds to the extracellular domain of CD74 variant 2 with an EC 50  of less than about 400 ng/mL; or   (c) both of (a) and (b),   
       when determined by enzyme-linked immunosorbant assay. 
     
     
         63 . The method of  claim 57 , wherein the antibody binds to cynomolgous CD74. 
     
     
         64 . The method of  claim 57 , wherein the antibody is internalized after binding to CD74 expressed on the surface of a cell. 
     
     
         65 . The method of  claim 57 , wherein the antibody has an EC 50  of less than about 60 ng/mL in inducing killing of Raji cells in an anti-kappa ETA′ assay. 
     
     
         66 . The method of  claim 57 , wherein the antibody has an off-rate at 0° C. of 0.02 to 1.0 min −1 . 
     
     
         67 . The method of  claim 57 , wherein the antibody comprises a V L  region comprising the CDR1, 2 and 3 sequences of SEQ ID NO:24, AAS and SEQ ID NO:25, and
 a) a V H  region comprising the CDR1, 2 and 3 sequences of SEQ ID NO: 20, 21 and 22 (011);   b) a V H  region comprising the CDR1, 2 and 3 sequences of SEQ ID NOS: 8, 9 and 10 (005);   c) a V H  region comprising the CDR1, 2 and 3 sequences of SEQ ID NO: 12, 13 and 14 (006);   d) a V H  region comprising the CDR1, 2 and 3 sequences of SEQ ID NO: 16, 17 and 18 (008); or   e) a variant of any of said antibodies, which variant preferably has at most one, two or three amino acid modifications in the V H  and/or V L  region, more preferably amino acid substitutions, such as conservative amino acid substitutions in said sequences.   
     
     
         68 . The method of  claim 57 , wherein the antibody comprises:
 (a) a V H  region comprising the sequence of SEQ ID NO: 19 and a V L  region comprising the sequence of SEQ ID NO: 26 [011];   (b) a V H  region comprising the sequence of SEQ ID NO: 7 and a V L  region comprising the sequence of SEQ ID NO: 26 [005/011] (c) a V H  region comprising the sequence of SEQ ID NO: 7 and a V L  region comprising the sequence of SEQ ID NO: 23 [005];   (d) a V H  region comprising the sequence of SEQ ID NO: 11 and a V L  region comprising the sequence of SEQ ID NO: 26 [006]; or   (d) a V H  region comprising the sequence of SEQ ID NO: 15 and a V L  region comprising the sequence of SEQ ID NO: 26 [008].   
     
     
         69 . The method of  claim 68 , wherein the antibody is a human monoclonal antibody. 
     
     
         70 . The method of  claim 69 , wherein the antibody has an isotype selected from IgG1 and IgG4. 
     
     
         71 . The method of  claim 57 , wherein the antibody is conjugated to a therapeutic moiety. 
     
     
         72 . The method of  claim 71 , wherein the antibody is conjugated to the therapeutic moiety via a linker attached to sulphydryl residues in the antibody, obtained by at least partial reduction of the antibody. 
     
     
         73 . The method of  claim 71 , wherein the therapeutic moiety is a cytotoxic moiety, a radioisotope, a chemotherapeutic agent, a lytic peptide or a cytokine. 
     
     
         74 . The method of  claim 73 , wherein the therapeutic moiety is a cytotoxic moiety. 
     
     
         75 . The method of  claim 74 , wherein the cytotoxic moiety is selected from the group consisting of taxol; cytochalasin B; gramicidin D; ethidium bromide; emetine; mitomycin; etoposide; tenoposide; vincristine; vinblastine; colchicin; doxorubicin; daunorubicin; dihydroxy anthracin dione; maytansine or an analog or derivative thereof; an auristatin or a functional peptide analog or derivative thereof dolastatin 10 or 15 or an analogue thereof; irinotecan or an analogue thereof; mitoxantrone; mithramycin; actinomycin D; 1-dehydrotestosterone; a glucocorticoid; procaine; tetracaine; lidocaine; propranolol; puromycin; calicheamicin or an analog or derivative thereof; an antimetabolite such as methotrexate, 6 mercaptopurine, 6 thioguanine, cytarabine, fludarabin, 5 fluorouracil, decarbazine, hydroxyurea, asparaginase, gemcitabine, or cladribine; an alkylating agent such as mechlorethamine, thioepa, chlorambucil, melphalan, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, dacarbazine (DTIC), procarbazine, mitomycin C; a platinum derivative such as cisplatin or carboplatin; duocarmycin A, duocarmycin SA, rachelmycin (CC-1065), or an analog or derivative thereof; an antibiotic such as dactinomycin, bleomycin, daunorubicin, doxorubicin, idarubicin, mithramycin, mitomycin, mitoxantrone, plicamycin, anthramycin (AMC)); pyrrolo[2,1-c][1,4]-benzodiazepines (PDB); diphtheria toxin and related molecules such as diphtheria A chain and active fragments thereof and hybrid molecules, ricin toxin such as ricin A or a deglycosylated ricin A chain toxin, cholera toxin, a Shiga-like toxin such as SLT I, SLT II, SLT IIV, LT toxin, C3 toxin, Shiga toxin, pertussis toxin, tetanus toxin, soybean Bowman-Birk protease inhibitor,  Pseudomonas  exotoxin, alorin, saporin, modeccin, gelanin, abrin A chain, modeccin A chain, alpha-sarcin,  Aleurites fordii  proteins, dianthin proteins,  Phytolacca americana  proteins such as PAPI, PAPII, and PAP-S,  momordica charantia  inhibitor, curcin, crotin,  sapaonaria officinalis  inhibitor, gelonin, mitogellin, restrictocin, phenomycin, and enomycin toxins; ribonuclease (RNase); DNase I, Staphylococcal enterotoxin A; pokeweed antiviral protein; diphtherin toxin; and  Pseudomonas  endotoxin. 
     
     
         76 . The method of  claim 74 , wherein the antibody is conjugated to a cytotoxic moiety selected from the group consisting of an anthracycline, a pyrrolo[2,1-c][1,4]-benzodiazepine, maytansine, calicheamicin, duocarmycin, rachelmycin (CC-1065), dolastatin 10 or 15, irinotecan, or from an analog, derivative, or prodrug of any thereof. 
     
     
         77 . The method of  claim 74 , wherein the cytotoxic moiety is an auristatin or a functional peptide analog or derivate thereof. 
     
     
         78 . The method of  claim 73 , wherein the antibody is conjugated to a cytokine selected from the group consisting of IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, IL-13, IL-15, IL-18, IL-23, IL-24, IL-27, IL-28a, IL-28b, IL-29, KGF, IFNα, IFNβ, IFNγ, GM-CSF, CD40L, Flt3 ligand, stem cell factor, ancestim, and TNFα. 
     
     
         79 . The method of  claim 57 , wherein the antibody is a multispecific antibody and comprises at least one second antigen-binding region having a different binding specificity. 
     
     
         80 . The method of  claim 79 , wherein the antibody is a bispecific antibody. 
     
     
         81 . The method of  claim 80 , wherein the second antigen-binding region has binding specificity for an antigen on a human effector cell. 
     
     
         82 . The method of  claim 80 , wherein, in the bispecific antibody
 the first antigen-binding region is linked to a first Fc-region having an amino acid substitution at a position selected from the group consisting of 366, 368, 370, 399, 405, 407 and 409, and the second antigen-binding region is linked to a second Fc-region having an amino acid substitution at a position selected from the group consisting of 366, 368, 370, 399, 405, 407 and 409, and   the first and second Fc-regions are not substituted in the same positions.   
     
     
         83 . The method of  claim 57 , wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, endometrial/cervical cancer, gastric cancer, head and neck cancer, lung cancer, malignant glioma, malignant melanoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, liver cancer, thymus cancer, malignant fibrous histiosarcoma, acoustic schwannoma, pituitary adenoma, and an adenoma. 
     
     
         84 . The method of  claim 57 , wherein the cancer is selected from the group consisting of malignant lymphoma, B cell chronic lymphocytic leukemia (B-CLL), chronic myeloid leukemia (CML) in blast phase, non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), monocytiod B cell lymphoma (MBCL), hairy-cell leukemia (HCL), and T cell lymphoma. 
     
     
         85 . The method of  claim 84 , wherein the cancer is NHL. 
     
     
         86 . The method of  claim 84 , wherein the cancer is MM. 
     
     
         87 . The method of  claim 83 , wherein the cancer is ovarian cancer. 
     
     
         88 . The method of  claim 83 , wherein the cancer is breast cancer. 
     
     
         89 . The method of  claim 83 , wherein the cancer is pancreatic cancer. 
     
     
         90 . The method of  claim 83 , wherein the cancer is selected from prostate cancer, gastric cancer, and colorectal cancer. 
     
     
         91 . The method of  claim 57 , comprising administering the antibody in combination with at least one further therapeutic agent. 
     
     
         92 . The method of  claim 91 , wherein the at least one further therapeutic agent is selected from a second antibody or ADC; a chemotherapeutic agent; an inhibitor of angiogenesis, neovascularization, and/or other vascularization; an anti-cancer immunogen; a cytokine or chemokine; a cell cycle control or apoptosis regulator; a hormonal regulating agent; an anti-anergic agent; a tumor suppressor gene-containing nucleic acid or vector; an anti-cancer nucleic acid; a virus or viral proteins; immune system cells; a differentiation inducing agent; a CD74 up-regulating agent; and an anti-inflammatory, immunosuppressive and/or immunomodulatory agent; or a combination of any thereof. 
     
     
         93 . The method of  claim 92 , wherein at least one therapeutic agent is selected from a CD20-specific antibody, a CD138-specific antibody, a CD38-specific antibody, an anti-VEGF-A antibody, melphalanan, lenalidomide, bortezomib, fluorouracil, gemticabine, irinotecan, cisplatin, or a derivative or analog thereof. 
     
     
         94 . A method for detecting the presence of CD74 antigen, or a cell expressing CD74, in a sample comprising contacting the sample with a CD74 specific antibody under conditions that allow for binding of the CD74 specific antibody to CD74 in the sample; and analyzing whether a complex has been formed, wherein the antibody binds to the same epitope on variants 1 and 2 of human CD74 as at least one antibody selected from:
 (a) an antibody comprising a VH region comprising the sequence of SEQ ID NO:19 and a VL region comprising the sequence of SEQ ID NO:26 [011];   (b) an antibody comprising a VH region comprising the sequence of SEQ ID NO:7 and a VL region comprising the sequence of SEQ ID NO:23 [005];   (c) an antibody comprising a VH region comprising the sequence of SEQ ID NO:11 and a VL region comprising the sequence of SEQ ID NO:26 [006]; and   (d) an antibody comprising a VH region comprising the sequence of SEQ ID NO:15 and a VL region comprising the sequence of SEQ ID NO:26 [008].   
     
     
         95 . The method of  claim 94 , wherein the sample is a biological sample. 
     
     
         96 . The method of  claim 95 , wherein the biological sample has been taken from a patient, and the biological sample is known or suspected of containing CD74 antigen and/or cells expressing CD74. 
     
     
         97 . The method of  claim 96 , wherein the patient suffers from a disease in which cells expressing CD74 are indicative of disease or involved in the pathogenesis. 
     
     
         98 . The method of  claim 97 , wherein the disease is cancer. 
     
     
         99 . The method of  claim 94 , wherein the analyzing step comprises one or more of ELISA, RIA, FACS assays, plasmon resonance assays, chromatographic assays, tissue immunohistochemistry, Western blot and immunoprecipitation. 
     
     
         100 . The method of  claim 99 , wherein the antibody is labeled with a detectable substance or is detected by a second antibody labeled with a detectable substance. 
     
     
         101 . The method of  claim 100 , wherein the detectable substance is selected from an enzyme, a prosthetic group, a fluorescent material, a luminescent material, and a radioactive material. 
     
     
         102 . The method of  claim 94 , wherein the antibody
 (a) binds to the extracellular domain of CD74 variant 1 with an EC 50  of less than about 500 ng/mL;   (b) binds to the extracellular domain of CD74 variant 2 with an EC 50  of less than about 400 ng/mL; or   (c) both of (a) and (b),   
       when determined by enzyme-linked immunosorbant assay. 
     
     
         103 . The method of  claim 94 , wherein the antibody binds to cynomolgous CD74. 
     
     
         104 . The method of  claim 94 , wherein the antibody is internalized after binding to CD74 expressed on the surface of a cell. 
     
     
         105 . The method of  claim 94 , wherein the antibody has an EC 50  of less than about 60 ng/mL in inducing killing of Raji cells in an anti-kappa ETA′ assay. 
     
     
         106 . The method of  claim 94 , wherein the antibody has an off-rate at 0° C. of 0.02 to 1.0 min −1 . 
     
     
         107 . The method of  claim 94 , wherein the antibody comprises a V L  region comprising the CDR1, 2 and 3 sequences of SEQ ID NO:24, AAS and SEQ ID NO:25, and
 a) a V H  region comprising the CDR1, 2 and 3 sequences of SEQ ID NO: 20, 21 and 22 (011);   b) a V H  region comprising the CDR1, 2 and 3 sequences of SEQ ID NOS: 8, 9 and 10 (005);   c) a V H  region comprising the CDR1, 2 and 3 sequences of SEQ ID NO: 12, 13 and 14 (006);   d) a V H  region comprising the CDR1, 2 and 3 sequences of SEQ ID NO: 16, 17 and 18 (008); or   e) a variant of any of said antibodies, which variant preferably has at most one, two or three amino acid modifications in the V H  and/or V L  region, more preferably amino acid substitutions, such as conservative amino acid substitutions in said sequences.   
     
     
         108 . The method of  claim 94 , wherein the antibody comprises:
 (a) a V H  region comprising the sequence of SEQ ID NO: 19 and a V L  region comprising the sequence of SEQ ID NO: 26 [011];   (b) a V H  region comprising the sequence of SEQ ID NO: 7 and a V L  region comprising the sequence of SEQ ID NO: 26 [005/011]   (c) a V H  region comprising the sequence of SEQ ID NO: 7 and a V L  region comprising the sequence of SEQ ID NO: 23 [005];   (d) a V H  region comprising the sequence of SEQ ID NO: 11 and a V L  region comprising the sequence of SEQ ID NO: 26 [006]; or   (d) a V H  region comprising the sequence of SEQ ID NO: 15 and a V L  region comprising the sequence of SEQ ID NO: 26 [008].   
     
     
         109 . The method of  claim 108 , wherein the antibody is a human monoclonal antibody. 
     
     
         110 . The method of  claim 109 , wherein the antibody has an isotype selected from IgG1 and IgG4. 
     
     
         111 . The method of  claim 98 , wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, endometrial/cervical cancer, gastric cancer, head and neck cancer, lung cancer, malignant glioma, malignant melanoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, liver cancer, thymus cancer, malignant fibrous histiosarcoma, acoustic schwannoma, pituitary adenoma, and an adenoma. 
     
     
         112 . The method of  claim 98 , wherein the cancer is selected from the group consisting of malignant lymphoma, B cell chronic lymphocytic leukemia (B-CLL), chronic myeloid leukemia (CML) in blast phase, non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), monocytiod B cell lymphoma (MBCL), hairy-cell leukemia (HCL), and T cell lymphoma. 
     
     
         113 . The method of  claim 112 , wherein the cancer is NHL. 
     
     
         114 . The method of  claim 112 , wherein the cancer is MM. 
     
     
         115 . The method of  claim 112 , wherein the cancer is ovarian cancer. 
     
     
         116 . The method of  claim 107 , wherein the cancer is breast cancer. 
     
     
         117 . The method of  claim 107 , wherein the cancer is pancreatic cancer. 
     
     
         118 . The method of  claim 107 , wherein the cancer is selected from prostate cancer, gastric cancer, and colorectal cancer. 
     
     
         119 . A method for the in vivo imaging of a CD74-expressing tissue, comprising administering an antibody which binds to the same epitope on variants 1 and 2 of human CD74 as at least one antibody selected from
 (a) an antibody comprising a VH region comprising the sequence of SEQ ID NO:19 and a VL region comprising the sequence of SEQ ID NO:26 [011];   (b) an antibody comprising a VH region comprising the sequence of SEQ ID NO:7 and a VL region comprising the sequence of SEQ ID NO:23 [005];   (c) an antibody comprising a VH region comprising the sequence of SEQ ID NO:11 and a VL region comprising the sequence of SEQ ID NO:26 [006]; and   (d) an antibody comprising a VH region comprising the sequence of SEQ ID NO:15 and a VL region comprising the sequence of SEQ ID NO:26 [008],   wherein the antibody is conjugated to at least one of a radioisotope, a radio-opaque agent, a dye, a contrast agent, a fluorescent compound or molecule and a paramagnetic ion.   
     
     
         120 . The method of  claim 115 , wherein the CD74-expressing tissue is a tumor. 
     
     
         121 . A kit for detecting the presence of CD74 antigen or a cell expressing CD74, in a sample, the kit comprising:
 a CD74 specific antibody, and   instructions for use of the kit,   wherein the antibody binds to the same epitope on variants 1 and 2 of human CD74 as at least one antibody selected from:   (a) an antibody comprising a VH region comprising the sequence of SEQ ID NO:19 and a VL region comprising the sequence of SEQ ID NO:26 [011];   (b) an antibody comprising a VH region comprising the sequence of SEQ ID NO:7 and a VL region comprising the sequence of SEQ ID NO:23 [005];   (c) an antibody comprising a VH region comprising the sequence of SEQ ID NO:11 and a VL region comprising the sequence of SEQ ID NO:26 [006]; and   (d) an antibody comprising a VH region comprising the sequence of SEQ ID NO:15 and a VL region comprising the sequence of SEQ ID NO:26 [008].   
     
     
         122 . The kit of  claim 121 , further comprising one or more reagents for detecting binding of the CD74-specific antibody to CD74. 
     
     
         123 . The kit of  claim 122 , wherein the reagents comprise one or more of a fluorescent tag, an enzymatic tag, a secondary antibody and reagents for enzymatic reactions, wherein the enzymatic reactions produce a product that may be visualized. 
     
     
         124 . The kit of  claim 121 , wherein the antibody is labeled with a detectable substance.