Anti-death receptor antibodies and methods of use thereof

Abstract

The present invention relates to monospecific or bispecific antibody molecules that specifically bind antigens of Death Receptors, which are members of the tumor necrosis factor (TNF) receptor Superfamily (TNFR-SF) with an intracellular death domain. The invention relates in particular to antibody molecules of the IgG1 isotype having a mutation in the Fc region that enhances clustering of IgG molecules after target binding. The invention further relates to a combination of antibody molecules binding different epitopes on one or more specific Death Receptors. The invention also relates to pharmaceutical compositions containing these molecules and the treatment of cancer using these compositions.

1 . A method for increasing the apoptotic activity of an antibody comprising a human IgG Fc region and an antigen binding region binding to a death receptor comprising an intracellular death domain, the method comprising introducing into the Fc region of the antibody a mutation at an amino acid position corresponding to position E430, E345, S440, and/or Y436 in human IgG1, wherein the antibody induces a higher level of apoptosis relative to the same antibody without the mutation, and wherein the positions are numbered according to the EU Index. 
     
     
         2 - 4 . (canceled) 
     
     
         5 . The method according to  claim 1 , wherein the Fc region of the antibody comprises a mutation selected from the group consisting of: E430G, E345K, E430S, E430F, E430T, E345Q, E345R, E345Y, S440W, S440Y, and Y436I. 
     
     
         6 - 8 . (canceled) 
     
     
         9 . The method according to  claim 1 , wherein the Fc region of the antibody comprises a further mutation in an amino acid position corresponding to position K439 in human IgG1. 
     
     
         10 - 13 . (canceled) 
     
     
         14 . The method according to  claim 1 , wherein the death receptor comprising an intracellular death domain is selected from the group consisting of: FAS, DR4, DR5, TNFR1, DR6, DR3, EDAR, and NGFR. 
     
     
         15 . (canceled) 
     
     
         16 . The method according to a  claim 1 , wherein the death receptor comprising an intracellular death domain is DR4. 
     
     
         17 . The method according to  claim 1 , wherein the antibody is an IgG1, IgG2, IgG3, IgG4, IgE, IgD, or IgM isotype. 
     
     
         18 . The method according to a  claim 1 , wherein the antibody is an IgG1 isotype. 
     
     
         19 . The method according to  claim 1 , wherein the antibody is an IgG1m(f), IgG1m(a), IgG1m(z), IgG1m(x) allotype or mixed allotype. 
     
     
         20 . The method according to  claim 1 , wherein the antibody is a monoclonal antibody. 
     
     
         21 . The method according to  claim 1 , wherein the antibody is human, humanized, or chimeric. 
     
     
         22 . The method according to  claim 1 , wherein the antibody is agonistic. 
     
     
         23 - 51 . (canceled) 
     
     
         52 . A method of treating an individual having a cancer, an infectious disease, an autoimmune disease, or cardiovascular anomalies, the method comprising administering to said individual an effective amount of an antibody comprising an Fc region of a human immunoglobulin IgG and an antigen binding region binding to a death receptor comprising an intracellular death domain, wherein the Fc region comprises a mutation at an amino acid position corresponding to position E430, E345, S440, and/or Y436 in human IgG1, wherein the antibody induces a higher level of apoptosis relative to the same antibody without the mutation, and wherein the positions are numbered according to the EU Index. 
     
     
         53 . The method according to  claim 52 , further comprising administering an additional therapeutic agent. 
     
     
         54 . The method according to  claim 53 , wherein the additional therapeutic agent is one or more anti-cancer agent(s) selected from the group consisting of chemotherapeutics, kinase inhibitors, apoptosis-modulating agents, RAS inhibitors, proteasome inhibitors, histone deacetylase inhibitors, nutraceuticals, cytokines, antibodies or antibody mimetics, and antibody-drug conjugates. 
     
     
         55 - 57 . (canceled) 
     
     
         58 . The method of  claim 52 , wherein the cancer is selected from a colorectal cancer, bladder cancer, osteosarcoma, chondrosarcoma, breast cancer, cancers of the central nervous system, cervical cancer, endometrium cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, sarcoma, skin cancer, leukemia, lymphoma, and myelodysplastic syndrome. 
     
     
         59 . An antibody comprising an Fc region of a human immunoglobulin IgG and an antigen-binding region which binds to a death receptor comprising an intracellular death domain, wherein the Fc region comprises a mutation at an amino acid position corresponding to position E430, E345, S440, and/or Y436 in a human IgG1, and wherein the positions are numbered according to EU Index. 
     
     
         60 . The antibody according to  claim 59 , wherein the death receptor comprising an intracellular death domain is selected from the group consisting of: FAS, DR4, DR5, TNFR1, DR6, DR3, EDAR, and NGFR. 
     
     
         61 . A multispecific antibody comprising one or more antigen binding regions of an antibody according to  claim 59 . 
     
     
         62 . A composition comprising at least one antibody according to  claim 59 . 
     
     
         63 . The composition according to  claim 62 , which comprises:
 i) a first antibody, wherein the Fc region comprises a first mutation at an amino acid position corresponding to E430 or E345 in human IgG1, and a further mutation at an amino acid position corresponding to K439 in human IgG1, EU numbering, and   ii) a second antibody, wherein the Fc region comprises a first mutation at an amino acid position corresponding to E430 or E345 in human IgG1, EU numbering, and a further mutation at an amino acid position corresponding to S440 in human IgG1.