Novel methods and antibodies for treating cancer

Abstract

The invention relates to novel methods for the treatment of tumors, comprising administration of a bispecific antibody or a combination of two or more non-cross-blocking antibodies that recognize the same target antigen or antigenic complex. In particular, the invention relates to a method for inducing complement-mediated cell killing in the treatment of a tumor, said method comprising combined administration, to a human being in need thereof, of a first antibody and a second antibody, wherein—said first antibody binds EGFR, —said second antibody binds EGFR, —said first and second antibody are non-cross-blocking, and—the dosage regimen is such that CDC is obtained at the tumor site.

1 . A method for inducing complement-mediated cell killing (CDC) in the treatment of a tumor, said method comprising combined administration, to a human being in need thereof, of a first antibody and a second antibody, wherein
 said first antibody binds EGFR,   said second antibody binds EGFR,   said first and second antibody are non-cross-blocking, and   the dosage regimen is such that CDC is obtained at the tumor site.   
     
     
         2 . The method of  claim 1 , wherein said first antibody is an antibody which is capable of binding an EGFR epitope which is found on all wild-type-EGFR-expressing cells. 
     
     
         3 . The method of  claim 1 , wherein said first antibody binds to human EGFR with an equilibrium dissociation constant (KD) of at most 10 −8  M, preferably at most 10 −10  M. 
     
     
         4 . The method of  claim 1 , wherein said first antibody is an antibody which is capable of inducing ADCC at the tumor site in the absence of said second antibody. 
     
     
         5 . The method of  claim 1 , wherein said first antibody is selected from the group consisting of:
 an antibody which binds the same EGFR epitope as zalutumumab,   an antibody which binds the same EGFR epitope as cetuximab,   an antibody which binds the same EGFR epitope as panitumumab,   an antibody which binds the same EGFR epitope as nimotuzumab,   an antibody which binds the same EGFR epitope as matuzumab, and   an antibody which binds the same EGFR epitope as 528.   
     
     
         6 . The method of  claim 1 , wherein said first antibody is selected from the group consisting of:
 an antibody which comprises the same heavy chain CDR3 sequence as zalutumumab and binds the same EGFR epitope as zalutumumab,   an antibody which comprises the same heavy chain CDR3 sequence as cetuximab and binds the same EGFR epitope as cetuximab,   an antibody which comprises the same heavy chain CDR3 sequence as panitumumab and binds the same EGFR epitope as panitumumab,   an antibody which comprises the same heavy chain CDR3 sequence as nimotuzumab and binds the same EGFR epitope as nimotuzumab,   an antibody which comprises the same heavy chain CDR3 sequence as matuzumab and binds the same EGFR epitope as matuzumab, and   an antibody which comprises the same heavy chain CDR3 sequence as 528 and binds the same EGFR epitope as 528.   
     
     
         7 . The method of  claim 1 , wherein said first antibody is selected from the group consisting of:
 an antibody which comprises the same 6 CDR sequences as zalutumumab,   an antibody which comprises the same 6 CDR sequences as cetuximab,   an antibody which comprises the same 6 CDR sequences as panitumumab,   an antibody which comprises the same 6 CDR sequences as nimotuzumab,   an antibody which comprises the same 6 CDR sequences as matuzumab, and   an antibody which comprises the same 6 CDR sequences as 528.   
     
     
         8 . The method of  claim 1 , wherein said first antibody is selected from the group consisting of: zalutumumab, cetuximab, panitumumab, nimotuzumab, matuzumab and 528. 
     
     
         9 . The method of  claim 5 , wherein said first antibody is an antibody which binds the same EGFR epitope as zalutumumab and said second antibody is selected from the group consisting of:
 an antibody which binds the same EGFR epitope as nimotuzumab, and   an antibody which binds the same EGFR epitope as matuzumab.   
     
     
         10 . The method of  claim 5 , wherein said first antibody is an antibody which binds the same EGFR epitope as cetuximab and said second antibody is an antibody which binds the same EGFR epitope as matuzumab. 
     
     
         11 . The method of  claim 5 , wherein said first antibody is an antibody which binds the same EGFR epitope as panitumumab and said second antibody is an antibody which binds the same EGFR epitope as matuzumab. 
     
     
         12 . The method of  claim 5 , wherein said first antibody is an antibody which binds the same EGFR epitope as nimotuzumab and said second antibody is an antibody which binds the same EGFR epitope as matuzumab. 
     
     
         13 . The method of  claim 1 , wherein said second antibody is capable of binding an EGFR epitope which is found in tumor cells, but is not detectable in normal cells. 
     
     
         14 . The method of  claim 13 , wherein said EGFR epitope does not demonstrate any amino acid sequence alterations or substitutions as compared to wild-type EGFR. 
     
     
         15 . The method of  claim 13 , wherein said second antibody binds an EGFR epitope which is located within the region comprising residues 273-501 of EGFR. 
     
     
         16 . The method of  claim 1 , wherein said second antibody binds an EGFR epitope, which is located within the region comprising residues 287-302 of EGFR. 
     
     
         17 . The method of  claim 1 , wherein said second antibody is cross-blocking with ch806. 
     
     
         18 . The method of  claim 1 , wherein said second antibody binds the same EGFR epitope as ch806. 
     
     
         19 . The method of  claim 18 , wherein the second antibody comprises SEQ ID NO:3 and one or more or all of SEQ ID NO: 1, 2, 4, 5 and 6. 
     
     
         20 . The method of  claim 18 , wherein the second antibody is ch806. 
     
     
         21 . The method of  claim 13 , wherein the second antibody is MR1-1. 
     
     
         23 . The method of  claim 1 , wherein said second antibody binds to EGFR-vIII with a KD which is at least 10 fold lower than the KD for binding to wild-type EGFR. 
     
     
         24 . The method of  claim 1 , wherein the first and/or the second antibody is a human antibody. 
     
     
         25 . The method of  claim 1 , wherein the dosage regimen of said first antibody comprises administration, at least once per 14 days, of a dosage of antibody of at least 0.1 mg/kg. 
     
     
         26 . The method of  claim 1 , wherein the dosage regimen of said second antibody comprises administration, at least once per 14 days, of a dosage of antibody of at least 0.1 mg/kg. 
     
     
         27 . The method of  claim 25 , wherein the administration of said first and second antibody is at least once per week. 
     
     
         28 . The method of  claim 1 , wherein the dosage regimen for said first antibody is lower than a standard dosage regimen for said first antibody. 
     
     
         29 . The method of  claim 1 , wherein the dosage regimen of said first antibody comprises administration of a total dosage per 14 days of between 0.01 mg/kg and 2 mg/kg. 
     
     
         30 . The method of  claim 1 , wherein the dosage regimen for said second antibody is lower than a standard dosage regimen for said second antibody. 
     
     
         31 . The method of  claim 1 , wherein the dosage regimen of said second antibody comprises administration of a total dosage per 14 days of between 0.01 mg/kg and 2 mg/kg. 
     
     
         32 . The method of  claim 1 , wherein the dosage regimen is such that substantially no CDC is obtained at non-tumor sites. 
     
     
         33 . The method of  claim 1 , wherein the dosage regimen ensures efficient inhibition of ligand binding at tumor sites. 
     
     
         34 . The method of  claim 13 , wherein the dosage regimen for said first antibody is a dosage regimen which comprises an equal or a higher dosage than a standard dosage regimen for said first antibody. 
     
     
         35 . The method of  claim 13 , wherein said first antibody is administered at an at least 2 times higher dose than said second antibody. 
     
     
         36 . The method of  claim 35 , wherein said first antibody is administered at a between 2 and 50 times higher dose than said second antibody. 
     
     
         37 . The method of  claim 13 , wherein:
 the dosage regimen of the first antibody comprises administration, at least once per 14 days, of a dose of antibody of at least 2 mg/kg, and   the dosage regimen of the second antibody comprises administration of a total dosage per 14 days of between 0.1 mg/kg and 1 mg/kg.   
     
     
         38 . The method of  claim 13 , wherein:
 the dosage regimen of the first antibody comprises administration, at least once per 14 days, of a dose of antibody of at least 4 mg/kg, and   the dosage regimen of the second antibody comprises administration of a total dosage per 14 days of between 0.1 mg/kg and 2 mg/kg.   
     
     
         39 . The method of  claim 1 , wherein said second antibody is administered at least 15 minutes before the first antibody. 
     
     
         40 . The method of  claim 1 , wherein the total duration of the treatment is at least one month. 
     
     
         41 . The method of  claim 1 , wherein said first and/or second antibody is administered parenterally, preferably intravenously. 
     
     
         42 . The method of  claim 1 , further comprising administration of a third antibody, wherein said third antibody is not cross-blocking with either of said first and second antibody. 
     
     
         43 . The method of  claim 1 , wherein said tumor is selected from the group consisting of: breast cancer tumor, bladder cancer tumor, uterine/cervical cancer tumor, esophageal cancer tumor, pancreatic cancer tumor, colorectal cancer tumor, kidney cancer tumor, ovarian cancer tumor, prostate cancer tumor, head and neck cancer tumor, non-small cell lung cancer tumor, stomach tumor, glioblastoma and other EGFR-expressing tumors. 
     
     
         44 . The method of  claim 1 , wherein the EGFR levels in the tumor cells to be treated are not below threshold for obtaining ADCC when treated with the first antibody without co-administration of the second antibody. 
     
     
         45 . The method of  claim 1 , comprising administration of one or more further therapies selected from chemotherapeutic agents, immunosuppressive agents, anti-inflammatory agents, anti-psoriasis agents, radiation therapy, hyperthermia, transplantation, surgery, sunlight therapy, and phototherapy. 
     
     
         46 . The method of  claim 1 , comprising administration of one or more further therapies selected from the group consisting of nitrogen mustards, aziridines, alkyl sulfonates, nitrosoureas, platinum complexes, non-classical alkylating agents, folate analogs, purine analogs, adenosine analogs, pyrimidine analogs, substituted ureas, antitumor antibiotics, epipodophyllotoxins, microtubule agents, camptothecin analogs, enzymes, cytokines, monoclonal antibodies, recombinant toxins and immunotoxins, cancer gene therapies, and cancer vaccines. 
     
     
         47 . The method of  claim 1 , comprising administration of one or more further therapies selected from the group consisting of immunosuppressive antibodies against MHC, CD2, CD3, CD4, CD7, CD28, B7, CD40, CD45, IFN-gamma, TNF-alpha, IL-4, IL-5, IL-6R, IL-7, IL-10, CD11a, CD20, and CD58 or antibodies against their ligands, soluble IL-15R, and IL-10. 
     
     
         48 . The method of  claim 1 , comprising administration of one or more further therapies selected from the group consisting of cyclosporine, azathioprine, mycophenolic acid, mycophenolate mofetil, corticosteroids, methotrexate, gold salts, sulfasalazine, antimalarials, brequinar, leflunomide, mizoribine, 15-deoxyspergualine, 6-mercaptopurine, cyclophosphamide, rapamycin, tacrolimus (FK-506), OKT3, anti-thymocyte globulin, transplantation, and surgery. 
     
     
         49 . The method of  claim 1 , comprising administration of one or more further therapies selected from the group consisting of aspirin, other salicylates, steroidal drugs, NSAIDs (nonsteroidal anti-inflammatory drugs), Cox-2 inhibitors, and DMARDs (disease modifying antirheumatic drugs). 
     
     
         50 . The method of  claim 1 , comprising administration of one or more further therapies selected from the group consisting of coal tar, A vitamin, anthralin, calcipotrien, tarazotene, corticosteroids, methotrexate, retinoids, cyclosporine, etanercept, alefacept, efaluzimab, 6-thioguanine, mycophenolate mofetil, tacrolimus (FK-506), hydroxyurea, sunlight therapy, and phototherapy. 
     
     
         51 . The method of  claim 1 , comprising administration of one or more tyrosine kinase inhibitors, such as gefitinib, erlotinib, XL-647, JNJ-26483327, vandetanib, BMS-599626, AZD-9935, AEE-788, BIBW-2992, ISU-101, HMPL-010, ON-012380, EKI-785, TX-2036, EHT-102, KI-6783, KI-6896 and LFM-A12. 
     
     
         52 . The method of  claim 1 , wherein said tumor is an EGFRvIII-expressing tumor. 
     
     
         53 . The method of  claim 1 , wherein the human being in need of the treatment is a human being who has been diagnosed to have tumors that exhibit EGFRvIII expression. 
     
     
         54 . A first antibody for use in the treatment of a tumor in combination with a second antibody, wherein
 said first antibody binds EGFR,   said second antibody binds EGFR,   said first and second antibody are non-cross-blocking, and   the dosage regimen is such that CDC is obtained at the tumor site.   
     
     
         55 . A first antibody for use in the treatment of a tumor in combination with a second antibody, wherein
 said first antibody binds EGFR,   said second antibody binds EGFR,   said first and second antibody are non-cross-blocking, and   the dosage regimen is such that CDC is obtained at the tumor site, wherein the first antibody, the second antibody and/or the treatment comprises one or more of the further features of  claim 2 .   
     
     
         56 . A second antibody for use in the treatment of a tumor in combination with a first antibody, wherein
 said first antibody binds EGFR,   said second antibody binds EGFR, and   said first and second antibody are non-cross-blocking, and   the dosage regimen is such that CDC is obtained at the tumor site.   
     
     
         57 . A second antibody for use in the treatment of a tumor in combination with a first antibody, wherein
 said first antibody binds EGFR,   said second antibody binds EGFR, and   said first and second antibody are non-cross-blocking, and   the dosage regimen is such that CDC is obtained at the tumor site, wherein the first antibody, the second antibody and/or the treatment comprises one or more of the further features of  claim 2 .   
     
     
         58 . Use of a first antibody and a second antibody for the preparation of a medicament for the treatment of a tumor, wherein
 said first antibody binds EGFR,   said second antibody binds EGFR, and   said first and second antibody are non-cross-blocking, and   the dosage regimen is such that CDC is obtained at the tumor site.   
     
     
         59 . Use of a first antibody and a second antibody for the preparation of a medicament for the treatment of a tumor, wherein
 said first antibody binds EGFR,   said second antibody binds EGFR, and   said first and second antibody are non-cross-blocking, and   the dosage regimen is such that CDC is obtained at the tumor site, comprising one or more of the further features of  claim 2 .   
     
     
         60 . A bispecific antibody comprising a first binding specificity which binds an EGFR epitope which is found on all wild-type-EGFR-expressing cells and a second binding specificity which binds an EGFR epitope which is found in tumor cells, but is not detectable in normal cells. 
     
     
         61 . The bispecific antibody of  claim 60 , wherein the second binding specificity binds an EGFR epitope is located within the region comprising residues 273-501 of EGFR, preferably the same EGFR epitope as bound by ch806, wherein said first and second binding specificity are non-cross-blocking. 
     
     
         62 . The bispecific antibody of  claim 60 , wherein the second binding specificity is specific for EGFR-vIII. 
     
     
         63 . The bispecific antibody of  claim 60 , wherein the antibody comprises a first binding specificity which binds an epitope selected from the group consisting of:
 the EGFR epitope bound by zalutumumab,   the EGFR epitope bound by cetuximab,   the EGFR epitope bound by panitumumab,   the EGFR epitope bound by nimotuzumab,   the EGFR epitope bound by matuzumab, and—the EGFR epitope bound by 528.   
     
     
         64 . A bispecific antibody as defined in  claim 60  for use as a medicament. 
     
     
         65 . A bispecific antibody as defined in  claim 60  for use as a medicament for the treatment of cancer. 
     
     
         66 . Use of a bispecific antibody as defined in  claim 60  for the preparation of a medicament for the treatment of cancer. 
     
     
         67 . A method for the treatment of cancer comprising administration of a bispecific antibody as defined in  claim 60 . 
     
     
         68 . The bispecific antibody of  claim 60 , wherein said tumor is selected from the group consisting of: breast cancer tumor, bladder cancer tumor, uterine/cervical cancer tumor, esophageal cancer tumor, pancreatic cancer tumor, colorectal cancer tumor, kidney cancer tumor, ovarian cancer tumor, prostate cancer tumor, head and neck cancer tumor, non-small cell lung cancer tumor, stomach cancer tumor, glioblastoma and other EGFR-expressing tumors.