Anti-cd134 (ox40) antibodies and uses thereof

Abstract

The invention provides antibodies that specifically bind to human CD134. Invention anti human CD134 antibodies specifically bind to the extracellular domain of human CD134, including non-OX40 ligand (OX40L) binding domains on human CD134, which is expressed on e.g. activated human conventional effector CD4 and/or CD8 T lymphocytes (Teffs) and on activated human suppressive regulatory CD4 T lymphocytes (Tregs). Invention anti-human CD134 antibodies are useful (e.g. to empower Teffs anti-cancer effector function and/or to inhibit Tregs suppressive function) for cancer treatment.

1 . to  48 . (canceled) 
     
     
         49 . An antibody that binds to human CD134, or an antigen-binding fragment thereof, wherein the antibody or antigen binding fragment thereof does not prevent human CD134(OX40) receptor binding to OX40 ligand (OX40L), and wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising:
 (a) a CDR1 comprising the amino acid sequence of SEQ ID NO:14;   (b) a CDR2 comprising the amino acid sequence of SEQ ID NO:15   (c) a CDR3 comprising the amino acid sequence of SEQ ID NO:16, and a light chain variable region comprising:   (a) a CDR1 comprising the amino acid sequence of SEQ ID NO:17;   (b) a CDR2 comprising the amino acid sequence of SEQ ID NO:18   (c) a CDR3 comprising the amino acid sequence of SEQ ID NO:19.   
     
     
         50 . The antibody or antigen binding fragment thereof of  claim 49 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:12 or a variant of that sequence having 1, 2 or 3 amino acid substitutions in the framework regions; and/or wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:13 or a variant of that sequence having 1, 2 or 3 amino acid substitutions in the framework regions. 
     
     
         51 . An antibody according to  claim 49 , which is a chimeric, humanized or deimmunized antibody, or antigen-binding fragment thereof. 
     
     
         52 . An antibody according to  claim 49 , which is an IgA, IgD, IgE, IgG or IgM antibody. 
     
     
         53 . An antibody according to  claim 52 , which is an IgG1, IgG2, IgG3 or IgG4 antibody. 
     
     
         54 . An antibody or antigen-binding fragment according to  claim 49 , which is a recombinant antibody or antigen binding fragment thereof. 
     
     
         55 . An antibody or antigen-binding fragment according to  claim 49 , which is a monoclonal antibody or antigen binding fragment thereof. 
     
     
         56 . An antibody or antigen-binding fragment according to  claim 49 , wherein said antigen-binding fragment of an antibody is a Fv fragment or an Fab-like fragment. 
     
     
         57 . A pharmaceutical composition comprising the antibody or antigen-binding fragment according to  claim 49  and one or more pharmaceutically acceptable diluents or excipients. 
     
     
         58 . A method of enhancing an immune response in a human subject, or treating cancer in a human subject in need thereof or reducing the size of a tumor or inhibiting the growth of cancer cells in a human subject or reducing or inhibiting the development of metastatic cancer in a human subject suffering from cancer, comprising administering to the human subject a therapeutically effective amount of the antibody or antigen-binding fragment according to  claim 49 . 
     
     
         59 . A method of treating cancer in a human subject in need thereof or reducing the size of a tumor or inhibiting the growth of cancer cells in a human subject or reducing or inhibiting the development of metastatic cancer in a human subject suffering from cancer, comprising administering to the human subject an antibody that binds human CD134, or an antigen-binding fragment thereof, comprising a heavy chain variable region comprising:
 (a) a CDR1 comprising the amino acid sequence of SEQ ID NO:6;   (b) a CDR2 comprising the amino acid sequence of SEQ ID NO:7;   (c) a CDR3 comprising the amino acid sequence of SEQ ID NO:8; and   a light chain variable region comprising:   (a) a CDR1 comprising the amino acid sequence of SEQ ID NO:9;   (b) a CDR2 comprising the amino acid sequence of SEQ ID NO:10; and   (c) a CDR3 comprising the amino acid sequence of SEQ ID NO:11.   
     
     
         60 . The method of  claim 59 , wherein the cancer is selected from the group consisting of lung cancer, prostate cancer, breast cancer, head and neck cancer, oesophageal cancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer, cervical cancer, uterine cancer, ovarian cancer, liver cancer, hematological cancer, or any disease or disorder characterized by uncontrolled cell growth. 
     
     
         61 . The method of  claim 59 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4 or a variant of that sequence having 1, 2 or 3 amino acid substitutions in the framework regions;
 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO:5 or a variant of that sequence having 1, 2 or 3 amino acid substitutions in the framework regions.   
     
     
         62 . The method according to  claim 59 , wherein the antibody is a chimeric, humanized or deimmunized antibody, or a fragment thereof. 
     
     
         63 . The method according to  claim 59 , wherein the antibody is an IgA, IgD, IgE, IgG or IgM antibody; or an IgG1, IgG2, IgG3 or IgG4 antibody. 
     
     
         64 . The method according to  claim 59 , wherein the antibody is a recombinant antibody or antigen-binding fragment thereof or a monoclonal antibody or antigen-binding fragment thereof. 
     
     
         65 . The method according to  claim 59 , wherein said antigen-binding fragment of an antibody is a Fv fragment or an Fab-like fragment. 
     
     
         66 . A method of enhancing an immune response in a human subject, comprising administering to the human subject a therapeutically effective amount of an antibody that binds human CD134, or an antigen-binding fragment thereof, comprising a heavy chain variable region comprising:
 (a) a CDR1 comprising the amino acid sequence of SEQ ID NO:6;   (b) a CDR2 comprising the amino acid sequence of SEQ ID NO:7   (c) a CDR3 comprising the amino acid sequence of SEQ ID NO:8, and a light chain variable region comprising:   (a) a CDR1 comprising the amino acid sequence of SEQ ID NO:9;   (b) a CDR2 comprising the amino acid sequence of SEQ ID NO:10   (c) a CDR3 comprising the amino acid sequence of SEQ ID NO:11.   
     
     
         67 . The method of  claim 66  wherein the enhanced immune response comprises an increase in the immunostimulator/effector function of T-effector cells, optionally as a result of proliferation of those cells, and/or a down-regulation of the immunosuppressor function of T-regulatory cells, optionally without expansion in numbers of those cells. 
     
     
         68 . The method of  claim 66 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4 or a variant of that sequence having 1, 2 or 3 amino acid substitutions in the framework regions; and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO:5 or a variant of that sequence having 1, 2 or 3 amino acid substitutions in the framework regions.