Anti-icos antibodies and their use in treatment of oncology, transplantation and autoimmune disease

Abstract

The present invention provides anti-human ICOS antibodies with increased effector function. The invention further relates to pharmaceutical compositions, immunotherapeutic compositions, and methods using therapeutic antibodies that bind to the human ICOS antigen and that may mediate ADCC, CDC, and/or antibody-dependent phagocytosis (opsonisation) for the treatment and prevention of T cell-mediated diseases and disorders, such as, but not limited to, chronic infection, autoimmune disease or disorder, inflammatory disease or disorder, graft-versus-host disease (GVHD), transplant rejection, and T cell proliferative disorder.

1 . An isolated anti-ICOS antibody comprising a VH domain, a VK domain and a variant Fc region, wherein the antibody mediates enhanced ADCC activity as compared to the level of ADCC activity mediated by a parent antibody comprising the VH and VK domains and a wild type Fc region, wherein said antibody is capable of depleting circulating ICOS-expressing T cells in a mammal for at least 14 days when administered as a single dose of 125 mg/m 2 , and wherein the variant Fc region is either:
 a. a variant Fc region comprising at least one substitution of an amino acid residue selected from the group consisting of: residue 239, 330, and 332, wherein the amino acid residue positions are determined according to the EU convention; or   b. an engineered Fc region, wherein the engineered Fc region comprises complex N-glycoside-linked sugar chains in which fucose is not bound to N-acetylglucosamine in the reducing end in the sugar chain.   
     
     
         2 . The antibody of  claim 1 , wherein the EC50 of the antibody as measured in an in vitro ADCC assay is at least about 7×lower than the EC50 value of the parent antibody. 
     
     
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         10 . The antibody of  1 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO:7 and the VK domain comprises the amino acid sequence of SEQ ID NO:2. 
     
     
         11 . A nucleic acid encoding the amino acid sequence of the antibody of  claim 1  wherein said nucleic acid comprises a nucleotide sequence selected from the group consisting of SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, and SEQ ID NO:31. 
     
     
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         13 . A vector comprising the nucleic acid of  claim 11 . 
     
     
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         15 . An isolated cell comprising the vector of  claim 13 . 
     
     
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         21 . A pharmaceutical composition comprising the antibody of  claim 1  in a pharmaceutically-acceptable carrier. 
     
     
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         23 . A method of treating an autoimmune disease or disorder or an inflammatory disease or disorder in a human, comprising administering to a human in need thereof a therapeutically-effective amount of the antibody of  claim 1 . 
     
     
         24 . The method of  claim 23 , wherein the autoimmune disease or disorder is SLE or scleroderma. 
     
     
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         29 . The method of  claim 23 , wherein the inflammatory disease or disorder is inclusion-body myositis (IBM), polymyositis (PM) or dermatomyositis (DM). 
     
     
         30 . A method of depleting ICOS expressing T cells in a human patient comprising administering to a human in need thereof a therapeutically-effective amount of the antibody of  claim 1 . 
     
     
         31 . The method of  claim 30 , wherein the depletion substantially persists for at least about 1, at least about 2, at least about 3 or at least about 4 weeks following the administration of the antibody. 
     
     
         32 . The method of  claim 30 , wherein at least about 95% of the T cells are depleted. 
     
     
         33 . The method of  claim 30 , wherein the ICOS expressing T cell is a memory T cell. 
     
     
         34 . The method of  claim 30 , wherein the ICOS expressing T cell is a circulating T cell. 
     
     
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         41 . A method of depleting circulating class switched B cells in a human patient comprising administering an effective amount of the antibody of  claim 1 . 
     
     
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         44 . The method of  claim 41 , wherein the depletion substantially persists for at least about 1, at least about 2, at least about 3 or at least about 4 weeks following the administration of the antibody. 
     
     
         45 . The method of  claim 41 , wherein at least about 95% of the circulating class switched B cells are depleted. 
     
     
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         56 . (canceled) 
     
     
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         59 . An isolated anti-ICOS antibody comprising a VH domain, a VK domain and a modified Fc region, wherein the antibody has complex N-glycoside-linked sugar chains bound to the modified Fc region in which fucose is not bound to N-acetylglucosamine in the reducing end in the sugar chain, wherein the antibody mediates enhanced ADCC activity as compared to the level of ADCC activity mediated by a parent antibody comprising the VH and VK domains and a non-engineered Fc region, and wherein said antibody is capable of depleting class switched B cells in a primate, and wherein the modified Fc region is either
 a. a variant Fc region comprising at least one substitution of an amino acid residue selected from the group consisting of: residue 239, 330, and 332, wherein the amino acid residue positions are determined according to the EU convention; or   b. an engineered Fc region, wherein the engineered Fc region comprises complex N-glycoside-linked sugar chains in which fucose is not bound to N-acetylglucosamine in the reducing end in the sugar chain.   
     
     
         60 . The antibody of  claim 59 , wherein the primate is a non-human primate. 
     
     
         61 . The antibody of  claim 59 , wherein the primate is a human. 
     
     
         62 . The antibody of  claim 59 , wherein the depletion substantially persists for at least about 1, at least about 2, at least about 3 or at least about 4 weeks following the administration of the antibody. 
     
     
         63 . The antibody of  claim 59 , wherein at least about 95% of the circulating class switched B cells are depleted.