Antibodies against g-csfr and uses thereof

Abstract

The present disclosure provides proteins comprising antigen binding domains of antibodies that bind to human granulocyte-colony stimulating factor receptor.

1 . A protein comprising an antigen binding site of an antibody, wherein the antigen binding site binds to human granulocyte-colony stimulating factor receptor (hG-CSFR) and neutralizes granulocyte-colony stimulating factor (G-CSF) signaling, and wherein the protein inhibits growth of colony forming units—granulocytes (CFU-G) from CD34 4+  bone marrow cells grown in the presence of G-CSF with an IC 50  of at least about 0.2 nM. 
     
     
         2 . The protein of  claim 1 , wherein the antigen binding site binds to both human and cynomolgus monkey granulocyte-colony stimulating factor receptor (G-CSFR) with a similar affinity and neutralizes granulocyte-colony stimulating factor (G-CSF) signaling. 
     
     
         3 . The protein of  claim 1  comprising at least a heavy chain variable region (V H ) and a light chain variable region (V L ), wherein the V H  and V L  bind to form a Fv comprising an antigen binding domain. 
     
     
         4 . The protein of  claim 3 , wherein the V H  and the V L  are in a single polypeptide chain or wherein the V I , and V H  are in separate polypeptide chains. 
     
     
         5 . The protein of  claim 4 , wherein if the V H  and V L  are in the same polypeptide chain, the protein is:
 (i) a single chain Fv fragment (scFv);   (ii) a dimeric scFv (di-scFv); or   (iii) at least one of (i) and/or (ii) linked to a constant region of an antibody, a Fc or a heavy chain constant domain (C H ) 2 and/or C H 3; or if the V H  and V L  are in separate polypeptide chains, the protein is:   (i) a diabody;   (ii) a triabody;   (iii) a tetrabody;   (iv) a Fab;   (v) a F(ab') 2 ;   (vi) a Fv;   (vii) an antibody; or (viii) one of (i) to (vi) linked to a constant region of an antibody, a Fc or a heavy chain constant domain (C H ) 2 and/or C H 3.   
     
     
         6 . The protein of  claim 1  which is chimeric, de-immunized, humanized, human or primatized. 
     
     
         7 . The protein of  claim 1 , which inhibits G-CSF-induced proliferation of a BaF3 cell expressing hG-CSFR with an IC 50  of at least about 0.5 nM. 
     
     
         8 . The protein of  claim 1 , which binds to a polypeptide comprising amino acids 1 to 311 of SEQ ID NO: 1 expressed as a fusion with an antibody Fc region with an affinity of at least about 0.5 nM, wherein affinity is determined in an assay in which the polypeptide immobilized and the protein or antibody contacted to the immobilized polypeptide. 
     
     
         9 . The protein of  claim 1 , which binds to hG-CSFR expressed on the surface of a cell at an affinity of at least about 1 nM. 
     
     
         10 . The protein of  claim 1  conjugated to another compound. 
     
     
         11 . A composition comprising the protein of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         12 . A method for treating or preventing a granulocyte-colony stimulating factor (G-CSF)-mediated condition in a subject, the method comprising administering the protein of  claim 1  to the subject. 
     
     
         13 . The method of  claim 12  comprising administering an amount of the protein or antibody sufficient to reduce the number of neutrophils in a subject without inducing neutropenia. 
     
     
         14 . The method of  claim 13 , wherein the amount of the protein is between 0.05 mg/kg and 30 mg/kg.