Antibody molecule for human gm-csf receptor alpha

Abstract

Binding members for alpha chain of receptor for granulocyte macrophage colony stimulating factor (GM-CSFRα), especially antibody molecules. Use of the binding members in treating inflammatory and autoimmune diseases, e.g. rheumatoid arthritis, asthma, allergic response, multiple sclerosis, myeloid leukaemia and atherosclerosis.

1 . An isolated binding member for human GM-CSFRα, wherein the binding member inhibits binding of GM-CSF to GM-CSFRα and wherein the binding member binds at least one residue of Tyr-Leu-Asp-Phe-Gln at positions 226 to 230 of human GM-CSFRα as shown in SEQ ID NO: 206. 
     
     
         2 . A binding member according to  claim 1 , which binds to human GM-CSFRα extra-cellular domain with an affinity (KD) of 5 nM or less in a surface plasmon resonance assay. 
     
     
         3 . A binding member according to  claim 1 , which comprises an antibody molecule. 
     
     
         4 . A binding member according to  claim 3 , comprising an antibody VH domain comprising a set of complementarity determining regions CDR1, CDR2 and CDR3 and a framework, wherein the set of complementarity determining regions comprises a CDR1 with amino acid sequence SEQ ID NO: 3 or SEQ ID NO: 173, a CDR2 with amino acid sequence SEQ ID NO: 4, and a CDR3 with amino acid sequence selected from the group consisting of SEQ ID NO: 5; SEQ ID NO: 15; SEQ ID NO: 25; SEQ ID NO: 35; SEQ ID NO: 45; SEQ ID NO: 55; SEQ ID NO: 65; SEQ ID NO: 75; SEQ ID NO: 85; SEQ ID NO: 95; SEQ ID NO: 105; SEQ ID NO: 115; SEQ ID NO: 125; SEQ ID NO: 135; SEQ ID NO: 145; SEQ ID NO: 155; SEQ ID NO: 165; SEQ ID NO: 175; SEQ ID NO: 185; and SEQ ID NO: 195; 
       or comprises that set of CDR sequences with one or two amino acid substitutions. 
     
     
         5 . A binding member according to  claim 3 , comprising an antibody VH domain comprising complementarity determining regions CDR1, CDR2 and CDR3 and a framework, and wherein Kabat residue H97 in VH CDR3 is S. 
     
     
         6 . A binding member according to  claim 5 , wherein VH CDR3 further comprises one or more of the following residues:
 V, N, A or L at Kabat residue H95;   S, F, H, P, T or W at Kabat residue H99;   A, T, P, S, V or H at Kabat residue H100B.   
     
     
         7 . A binding member according to  claim 6 , wherein Kabat residue H95 is V. 
     
     
         8 . A binding member according to  claim 6 , wherein Kabat residue H99 is S. 
     
     
         9 . A binding member according to  claim 6 , wherein Kabat residue H100B is A or T. 
     
     
         10 . A binding member according to any of  claim 6 , wherein VH CDR3 has an amino acid sequence selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 15, SEQ ID NO: 35, SEQ ID NO: 45, SEQ ID NO: 55, SEQ ID NO: 65, SEQ ID NO: 75, SEQ ID NO: 85, SEQ ID NO: 95, SEQ ID NO: 105, SEQ ID NO: 115, SEQ ID NO: 125, SEQ ID NO: 135, SEQ ID NO: 145, SEQ ID NO: 155, SEQ ID NO: 165, SEQ ID NO: 175, SEQ ID NO: 185 and SEQ ID NO: 195. 
     
     
         11 - 27 . (canceled) 
     
     
         28 . An isolated binding member for human GM-CSFRα of  claim 1 , wherein the binding member inhibits binding of GM-CSF to GM-CSFRα, and wherein the binding member binds human GM-CSFRα extra-cellular domain with an affinity (KD) of 5 nM or less in a surface plasmon resonance assay. 
     
     
         29 . A binding member according to  claim 28 , which comprises an antibody molecule. 
     
     
         30 . An isolated binding member for human GM-CSFRα, wherein the binding member inhibits binding of GM-CSF to GM-CSFRα, and wherein the binding member comprises a human or humanised antibody molecule that competes for binding the extracellular domain of human GM-CSFRα with an antibody molecule having a VH domain and a VL domain with amino acid sequences selected from the following:
 VH domain SEQ ID NO: 2 and VL domain SEQ ID NO: 7; 
 VH domain SEQ ID NO: 12 and VL domain SEQ ID NO: 17; 
 VH domain SEQ ID NO: 22 and VL domain SEQ ID NO: 17; 
 VH domain SEQ ID NO: 32 and VL domain SEQ ID NO: 17; 
 VH domain SEQ ID NO: 42 and VL domain SEQ ID NO: 17; 
 VH domain SEQ ID NO: 52 and VL domain SEQ ID NO: 57; 
 VH domain SEQ ID NO: 62 and VL domain SEQ ID NO: 17; 
 VH domain SEQ ID NO: 72 and VL domain SEQ ID NO: 17; 
 VH domain SEQ ID NO: 82 and VL domain SEQ ID NO: 17; 
 VH domain SEQ ID NO: 92 and VL domain SEQ ID NO: 17; 
 VH domain SEQ ID NO: 102 and VL domain SEQ ID NO: 107; 
 VH domain SEQ ID NO: 112 and VL domain SEQ ID NO: 117; 
 VH domain SEQ ID NO: 22 and VL domain SEQ ID NO: 127; 
 VH domain SEQ ID NO: 132 and VL domain SEQ ID NO: 137; 
 VH domain SEQ ID NO: 142 and VL domain SEQ ID NO: 147; 
 VH domain SEQ ID NO: 152 and VL domain SEQ ID NO: 157; 
 VH domain SEQ ID NO: 152 and VL domain SEQ ID NO: 167; 
 VH domain SEQ ID NO: 172 and VL domain SEQ ID NO: 177; 
 VH domain SEQ ID NO: 182 and VL domain SEQ ID NO: 187; or 
 VH domain SEQ ID NO: 192 and VL domain SEQ ID NO: 197. 
 
     
     
         31 . An isolated binding member for human GM-CSFRα, wherein the binding member inhibits binding of GM-CSF to GM-CSFRα and wherein the binding member comprises an antibody molecule comprising an antibody VH domain comprising a set of complementarity determining regions HCDR1, HCDR2 and HCDR3 and a framework, wherein the set of complementarity determining regions comprises an HCDR1 with amino acid sequence SEQ ID NO: 3 or SEQ ID NO: 173, an HCDR2 with amino acid sequence SEQ ID NO: 4, and an HCDR3 with amino acid sequence selected from the group consisting of SEQ ID NO: 5; SEQ ID NO: 15; SEQ ID NO: 25; SEQ ID NO: 35; SEQ ID NO: 45; SEQ ID NO: 55; SEQ ID NO: 65; SEQ ID NO: 75; SEQ ID NO: 85; SEQ ID NO: 95; SEQ ID NO: 105; SEQ ID NO: 115; SEQ ID NO: 125; SEQ ID NO: 135; SEQ ID NO: 145; SEQ ID NO: 155; SEQ ID NO: 165; SEQ ID NO: 175; SEQ ID NO: 185; and SEQ ID NO: 195. 
     
     
         32 . A binding member according  claim 3 , wherein the antibody molecule is a human or humanised antibody molecule. 
     
     
         33 . A binding member according to  claim 32 , wherein the VH domain framework is a human germline VH1 DP5 or VH3 DP47 framework. 
     
     
         34 . (canceled) 
     
     
         35 . An isolated antibody molecule for human GM-CSFRα of  claim 30 , which inhibits binding of GM-CSF to GM-CSFRα, and which comprises
 a VH domain with the VH domain amino acid sequence shown in SEQ ID NO: 52 or a variant thereof with one or two amino acid alterations, and 
 a VL domain with the VL domain amino acid sequence shown in SEQ ID NO: 57 or a variant thereof with one or two amino acid alterations; 
 wherein the amino acid alterations are selected from the group consisting of substitutions, insertions and deletions. 
 
     
     
         36 . (canceled) 
     
     
         37 . A binding member or an antibody molecule according to  claim 1 , which binds human GM-CSFRα extra-cellular domain with an affinity (KD) of 1 nM or less in a surface plasmon resonance assay. 
     
     
         38 - 48 . (canceled) 
     
     
         49 . A method for producing a binding member or an antibody molecule for human GM-CSFRα according to  claim 1 , the method comprising
 providing, by way of insertion, deletion or substitution of one or more amino acids in the amino acid sequence of a parent VH domain comprising HCDR1, HCDR2 and HCDR3, a VH domain which is an amino acid sequence variant of the parent VH domain; wherein 
 the parent VH CDR1 has an amino acid sequence SEQ ID NO: 3; 
 the parent VH CDR2 has an amino acid sequence SEQ ID NO: 4; and 
 the parent VH CDR3 has an amino acid sequence selected from the group consisting of SEQ ID NO: 5; SEQ ID NO: 15; SEQ ID NO: 25; SEQ ID NO: 35; SEQ ID NO: 45; SEQ ID NO: 55; SEQ ID NO: 65; SEQ ID NO: 75; SEQ ID NO: 85; SEQ ID NO: 95; SEQ ID NO: 105; SEQ ID NO: 115; SEQ ID NO: 125; SEQ ID NO: 135; SEQ ID NO: 145; SEQ ID NO: 155; SEQ ID NO: 165; SEQ ID NO: 185; and SEQ ID NO: 195; or wherein 
 the parent VH CDR1 has an amino acid sequence SEQ ID NO: 173, the parent VH CDR2 has an amino acid sequence SEQ ID NO: 4, and the parent VH CDR3 has an amino acid sequence SEQ ID NO: 175; 
 and 
 optionally combining the VH domain thus provided with one or more VL domains to provide one or more VH/VL combinations; and 
 testing the VH domain or the VH/VL combination or combinations to identify an antibody molecule for human GM-CSFRα. 
 
     
     
         50 . A method according to  claim 49  wherein said one or more VL domains is provided by way of insertion, deletion or substitution of one or more amino acids in the amino acid sequence of a parent VL domain comprising LCDR1, LCDR2 and LCDR3; wherein
 the parent VL CDR1 has an amino acid sequence SEQ ID NO: 8; 
 the parent VL CDR2 has an amino acid sequence SEQ ID NO: 9; and 
 the parent VL CDR3 has an amino acid sequence selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 20, SEQ ID NO: 30, SEQ ID NO: 60, SEQ ID NO: 120, SEQ ID NO: 130, SEQ ID NO: 140, SEQ ID NO: 150, SEQ ID NO: 160, SEQ ID NO: 170, SEQ ID NO: 180, SEQ ID NO: 190 and SEQ ID NO: 200. 
 
     
     
         51 - 54 . (canceled)