Anti-human folate receptor beta antibodies and methods of use

Abstract

Human anti-human folate receptor beta antibodies and antigen-binding fragments thereof are described, as well as method of using such antibodies and fragments to treat inflammatory disorders or cancers expressing cell surface FRβ.

What is claimed is: 
     
         1 . An isolated human monoclonal antibody, or an antigen-binding fragment thereof, that specifically binds human folate receptor beta (FRβ). 
     
     
         2 . The antibody or fragment of  claim 1  comprising:
 a heavy chain variable region (V H ) complementarity determining region (CDR) 1 comprising the amino acid sequence set forth in SEQ ID NO:1; 
 a V H  CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2; and 
 a V H  CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, 
 wherein the antibody or fragment has one or more properties selected from the group consisting of: 
 (a) the antibody or fragment does not detectably bind to human folate receptor alpha (FRα); 
 (b) the antibody or fragment binds to human macrophages but not to mouse macrophages; 
 (c) the antibody or fragment has a binding affinity (EC 50 ) of 20 nM; 
 (d) the antibody or fragment has a dissociation constant (Kd) of 6.39 nM; and 
 (e) the antibody mediates antibody-dependent cellular cytotoxicity (ADCC) of FRβ-expressing target cells. 
 
     
     
         3 . The antibody or fragment of  claim 2 , wherein said antibody or fragment binds to cell surface FRβ. 
     
     
         4 . The antibody or fragment of  claim 2 , wherein said antibody is an IgG1 antibody. 
     
     
         5 . The antibody or fragment of  claim 2 , wherein said antibody or fragment is de-fucosylated. 
     
     
         6 . The antibody or fragment of  claim 2 , wherein the fragment is a Fab antibody fragment, a F(ab′) 2  fragment, or a single chain antibody fragment (scFv). 
     
     
         7 . The antibody or fragment of  claim 2  conjugated with a pharmaceutical agent. 
     
     
         8 . The antibody or fragment of  claim 7 , wherein said pharmaceutical agent is a chemotherapeutic. 
     
     
         9 . The antibody or fragment of  claim 2  conjugated to a liposome. 
     
     
         10 . The antibody or fragment of  claim 9 , wherein said liposome comprises a pharmaceutical agent. 
     
     
         11 . The antibody or fragment of  claim 2  linked to a toxin. 
     
     
         12 . The antibody or fragment of  claim 11  wherein said antibody or fragment thereof is covalently linked to said toxin. 
     
     
         13 . The antibody or fragment of  claim 2  linked to a detectable moiety. 
     
     
         14 . The antibody or fragment of  claim 13 , wherein said detectable moiety is selected from the group consisting of a fluorescent moiety, a luminescent moiety, a radioactive moiety, a CT contrast agent, an MRI contrast agent, and biotin. 
     
     
         15 . The antibody or fragment of  claim 2 , wherein the antibody or fragment comprises one or more framework regions in SEQ ID NO:7. 
     
     
         16 . The antibody or fragment of  claim 2 , wherein the antibody or fragment comprises SEQ ID NO:10. 
     
     
         17 . The isolated antibody or fragment of  claim 2 , wherein the antibody or fragment comprises:
 a light chain variable region (V L ) CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4;   a V L  CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5; and   a V L  CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6.   
     
     
         18 . The isolated antibody or fragment of  claim 2 , wherein the antibody or fragment comprises:
 a light chain variable region (V L ) CDR1 comprising the amino acid sequence set forth in SEQ ID NO:14;   a V L  CDR2 comprising the amino acid sequence set forth in SEQ ID NO:15; and   a V L  CDR3 comprising the amino acid sequence set forth in SEQ ID NO:16.   
     
     
         19 . An isolated human monoclonal antibody, or an antigen-binding fragment thereof, that specifically binds human FRβ, the antibody or fragment comprising:
 a heavy chain variable region (V H ) CDR 1 comprising the amino acid sequence set forth in SEQ ID NO:1; 
 a V H  CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2; 
 a V H  CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3; 
 a light chain variable region (V L ) CDR1 comprising the amino acid sequence set forth in SEQ ID NO:14; 
 a V L  CDR2 comprising the amino acid sequence set forth in SEQ ID NO:15; and 
 a V L  CDR3 comprising the amino acid sequence set forth in SEQ ID NO:16. 
 
     
     
         20 . An isolated human monoclonal antibody, or an antigen-binding fragment thereof, that specifically binds human FRβ, the antibody or fragment comprising:
 a heavy chain variable region (V H ) CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1; 
 a V H  CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2; 
 a V H  CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3; 
 a light chain variable region (V L ) CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4; 
 a V L  CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5; and 
 a V L  CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6. 
 
     
     
         21 . A composition comprising the antibody or fragment of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         22 . A method of treating a patient having an inflammatory disorder, said method comprising administering to said patient, an amount of the composition of  claim 21  effective to reduce the number of FRβ positive macrophages and monocytes in said patient.