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 . 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 positions are numbered according to EU Index. 
     
     
         2 - 4 . (canceled) 
     
     
         5 . The antibody according to  claim 1 , wherein the Fc region 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 antibody according to  claim 1 , wherein the Fc region comprises a further mutation in an amino acid position corresponding to K439. 
     
     
         10 . The antibody according to  claim 1 , wherein the Fc region comprises a mutation at an amino acid position corresponding to E430 and/or E345 in a human IgG1, and wherein said Fc region comprises a further mutation at an amino acid position corresponding to S440, with the proviso that the mutation is not S440Y or S440W. 
     
     
         11 . The antibody according to  claim 9 , wherein the further mutation is selected from the group consisting of: K439E, K439D. 
     
     
         12 . The antibody according to  claim 10 , wherein the further mutation is selected from the group consisting of: S440K, S440R and S440H. 
     
     
         13 . The antibody according to  claim 1 , wherein the antibody further comprises a mutation selected from K439E or S440K. 
     
     
         14 . The antibody 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 - 16 . (canceled) 
     
     
         17 . The antibody according to  claim 1 , wherein the antibody is an IgG1, IgG2, IgG3, IgG4, IgE, IgD or IgM isotype. 
     
     
         18 - 19 . (canceled) 
     
     
         20 . The antibody according to  claim 1 , wherein the antibody is a monoclonal antibody. 
     
     
         21 . The antibody according to  claim 1 , wherein the antibody is human, humanized or chimeric. 
     
     
         22 . The antibody according to  claim 1 , wherein the antibody is agonistic. 
     
     
         23 . The antibody according to  claim 1 , wherein the antibody induces programmed cell death in a target cell. 
     
     
         24 - 25 . (canceled) 
     
     
         26 . A multispecific antibody comprising one or more antigen binding regions according to  claim 1 . 
     
     
         27 . The multispecific antibody according to  claim 26 , wherein said multispecific antibody is a bispecific antibody. 
     
     
         28 . The bispecific antibody according to  claim 27 , wherein said first antigen binding region and said second antigen binding region binds different epitopes on one or more members of a death receptor comprising an intracellular death domain selected from the group consisting of: FAS, DR4, DR5, TNFR1, DR6, DR3, EDAR and NGFR. 
     
     
         29 . (canceled) 
     
     
         30 . A composition comprising at least one antibody according to  claim 1  and a carrier. 
     
     
         31 . (canceled) 
     
     
         32 . A composition comprising a first antibody and a second antibody, wherein both the first and second antibodies are according to  claim 1 . 
     
     
         33 . The composition according to  claim 30 , 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.   
     
     
         34 . The composition according to  claim 33 , which comprises a first antibody wherein the further mutation is selected from the group of: K439E and K439D, and a second antibody wherein the further mutation is selected from the group of S440K, S440R or S440H. 
     
     
         35 . (canceled) 
     
     
         36 . The composition according to  claim 32 , wherein said first antibody and said second antibody bind different epitopes on one or more members of a death receptor comprising an intracellular death domain selected form the group consisting of: such as FAS, DR4, DR5, TNFR1, DR6, DR3, EDAR and NGFR. 
     
     
         37 - 45 . (canceled) 
     
     
         46 . A method of treating an infectious disease, autoimmune disease, or cardiovascular anomalies comprising administering to a subject in need thereof an effective amount of the composition of  claim 30 . 
     
     
         47 . A method of treating a solid tumor and/or hematological tumor comprising administering to a subject in need thereof an effective amount of the composition of  claim 30 . 
     
     
         48 . The method of  claim 47 , wherein the solid tumor is selected from the group consisting of 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, and skin cancer; and the hematological tumor is selected from the group consisting of leukemia, lymphoma, and multiple myeloma. 
     
     
         49 . (canceled) 
     
     
         50 . A method of inhibiting growth of FAS, DR4, DR5, TNFR1, DR6, DR3, EDAR or NGFR expressing tumors comprising administering to a subject in need thereof an effective amount of the composition of  claim 30 . 
     
     
         51 . A method of inducing apoptosis in FAS, DR4, DR5, TNFR1, DR6, DR3, EDAR or NGFR expressing tumors comprising administering to a subject in need thereof an effective amount of the composition of  claim 30 . 
     
     
         52 . A method of treating an individual having a cancer comprising administering to said individual an effective amount of the antibody of  claim 1 . 
     
     
         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 of chemotherapeutics, kinase inhibitors, apoptosis-modulating agents, RAS inhibitors, proteasome inhibitors, histone deacetylase inhibitors, antibodies or antibody mimetics, antibody-drug conjugates. 
     
     
         55 . A kit comprising the antibody of  claim 1 , and instructions for use. 
     
     
         56 - 57 . (canceled)