Humanized Anti-CD134 (OX40) Antibodies And Uses Thereof

Abstract

The invention provides antibodies that specifically bind to human CD134. 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). Humanized 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 .- 20 . (canceled) 
     
     
         21 . One or more isolated nucleic acid molecules encoding a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 98 or having 1, 2 or 3 amino acid substitutions in the VL of SEQ ID NO: 98 and encoding a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 134, or the amino acid sequence of SEQ ID NO:134 having 1, 2 or 3 amino acid substitutions. 
     
     
         22 . The one or more isolated nucleic acid molecules of  claim 21 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 97, optionally having 1, 2 or 3 amino acid substitutions in the VH of SEQ ID NO: 97. 
     
     
         23 . The one or more isolated nucleic acid molecules of  claim 21 , wherein the HCDR3 comprises the amino acid sequence of SEQ ID NOs: 8, 139 or 140. 
     
     
         24 . The one or more isolated nucleic acid molecules of  claim 23 , wherein the HCDR2 comprises the amino acid sequence of SEQ ID NOs: 7, 135, 136, 137 or 138. 
     
     
         25 . The one or more isolated nucleic acid molecules of  claim 24 , wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 6. 
     
     
         26 . The one or more isolated nucleic acid molecules of  claim 21 , wherein
 a. the VL comprises the amino acid sequence of SEQ ID NOs: 62 or 63; and the VH comprises the amino acid sequence of SEQ ID NOs: 64, 65, 66, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 149, 150 or 151, optionally having 1, 2 or 3 amino acid substitutions at the VH linear amino acid residue positions 11, 56 or 106; or   b. the VL and the VH comprise the amino acid sequences of
 i. SEQ ID NOs: 62 and 64, respectively; 
 ii. SEQ ID NOs: 62 and 65, respectively; 
 iii. SEQ ID NOs: 62 and 66, respectively; 
 iv. SEQ ID NOs: 63 and 64, respectively; 
 v. SEQ ID NOs: 63 and 65, respectively; or 
 vi. SEQ ID NOs: 63 and 66, respectively. 
   
     
     
         27 . The one or more isolated nucleic acid molecules of  claim 26 , wherein the VL comprises the amino acid sequence of SEQ ID NO:63 and the VH comprises the amino acid sequence of SEQ ID NO:66. 
     
     
         28 . The one or more isolated nucleic acid molecules of  claim 26 , wherein the 1, 2 or 3 amino acid substitutions at the VH linear amino acid residue positions are V11L, D56G, D56A, D56S, D56E, M106L or M106I. 
     
     
         29 . The one or more isolated nucleic acid molecules of  claim 21 , wherein the encoded antibody binds to an epitope of the extracellular domain of human CD134 comprising the amino acid sequence of SEQ ID NO: 35; SEQ ID NO: 36, or SEQ ID NO: 92. 
     
     
         30 . The one or more isolated nucleic acid molecules of  claim 21 , wherein the encoded antibody is humanized or deimmunized. 
     
     
         31 . The one or more isolated nucleic acid molecules of  claim 21 , wherein the encoded antibody is an agonist of CD134. 
     
     
         32 . The one or more isolated nucleic acid molecules of  claim 31 , wherein the encoded antibody is of IgG1, IgG2, IgG3 or IgG4 isotype. 
     
     
         33 . The one or more isolated nucleic acid molecules of  claim 32 , wherein the encoded antibody comprises a substitution in an Fc region. 
     
     
         34 . The one or more isolated nucleic acid molecules of  claim 33 , wherein the substitution modulates binding of the encoded antibody to an Fc gamma receptor (FcγR) or to a neonatal Fc receptor (FcRn). 
     
     
         35 . The one or more isolated nucleic acid molecules of  claim 34 , wherein the substitution comprises a S267E/L328F substitution, an E233D/G237D/H268D/P271G/A330R substitution, a V234A/G237A/P238S/H268A/V309L/A330S/P331S substitution, or a M252Y/S254T/T256E substitution, wherein residue numbering is according to the EU Index. 
     
     
         36 . One or more vectors comprising the one or more nucleic acid molecules of  claim 21 . 
     
     
         37 . A host cell comprising the one or more vectors of  claim 36 . 
     
     
         38 . An isolated nucleic acid molecule encoding an agonistic antibody that binds human CD134, comprising a light chain variable region (VL) and a heavy chain variable region (VH) comprising heavy chain complementarity determining regions (HCDR)s HCDR1, HCDR2 and HCDR3, and light chain complementarity determining regions (LCDR)s LCDR1, LCDR2 and LCDR3, wherein
 a. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 6;   b. the HCDR2 comprises the amino acid sequence of SEQ ID NOs:7, 135, 136, 137 or 138;   c. the HCDR3 comprises the amino acid sequence of SEQ ID NOs: 8, 139 or 140;   d. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 9;   e. the LCDR2 comprises the amino acid sequence of SEQ ID NO: 10; and   f. the LCDR3 comprises the amino acid sequence of SEQ ID NO: 11;   
       with the proviso that the antibody does not comprise the VH comprising the HCDR1, the HCDR2 and the HCDR3 amino acid sequences of SEQ ID NO:s 6, 7 and 8, and the VL comprising the LCDR1, the LCDR2 and the LCDR3 amino acid sequences of SEQ ID NOs: 9, 10 and 11.