Human Antigen Binding Proteins That Bind To a Complex Comprising beta-Klotho and an FGF Receptor

Abstract

The present invention provides compositions and methods relating to or derived from antigen binding proteins capable of inducing B-Klotho, and or FGF21-like mediated signaling. In embodiments, the antigen binding proteins specifically bind to a complex comprising β-Klotho and at least one of (i) FGFR1c, (ii) FGFR2c and (iii) FGFR3c. In some embodiments the antigen binding proteins induce FGF21-like signaling. In some embodiments, an antigen binding protein is a fully human, humanized, or chimeric antibodies, binding fragments and derivatives of such antibodies, and polypeptides that specifically bind to a complex comprising β-Klotho and at least one of (i) FGFR1c, (ii) FGFR2c and (iii) FGFR3c. Other embodiments provide nucleic acids encoding such antigen binding proteins, and fragments and derivatives thereof, and polypeptides, cells comprising such polynucleotides, methods of making such antigen binding proteins, and fragments and derivatives thereof, and polypeptides, and methods of using such antigen binding proteins, fragments and derivatives thereof, and polypeptides, including methods of treating or diagnosing subjects suffering from type 2 diabetes, obesity, NASH, metabolic syndrome and related disorders or conditions.

1 - 23 . (canceled) 
     
     
         24 . A method of preventing or treating a condition in a subject in need of such treatment comprising administering a therapeutically effective amount of isolated antigen binding protein that induces FGF21-mediated signaling, wherein the antigen binding protein comprises a light chain CDR1 comprising a sequence of SEQ ID NO: 821, a light chain CDR2 comprising a sequence of SEQ ID NO: 900, a light chain CDR3 comprising a sequence of SEQ ID NO: 954, a heavy chain CDR1 comprising a sequence of SEQ ID NO: 611, a heavy chain CDR2 comprising a sequence of SEQ ID NO: 664, and a heavy chain CDR3 comprising a sequence of SEQ ID NO: 741 to the subject, wherein the condition is treatable by lowering one or more of blood glucose, insulin or serum lipid levels. 
     
     
         25 . The method of  claim 24 , wherein the antigen binding protein comprises one or more of:
 (a) a light chain variable domain sequence comprising V L 47 of Table 2A (SEQ ID NO. 263);   (b) a heavy chain variable domain sequence comprising V H 46 of Table 2B (SEQ ID NO: 361); or   (c) a combination comprising a light chain variable domain of (a) and a heavy chain variable domain of (b).   
     
     
         26 . The method of  claim 25 , wherein the light chain variable domain and the heavy chain variable domain comprise V L 47 and V H 46. 
     
     
         27 . The method of  claim 26 , wherein the antigen binding protein comprises:
 (a) a kappa light chain constant sequence of SEQ ID NO: 12   (b) a lambda light chain constant sequence of SEQ ID NO: 13   (c) a heavy chain constant sequence of SEQ ID NO: 11; or   (d) (i) the kappa light chain constant sequence of SEQ ID NO: 12 or the lambda light chain constant sequence of SEQ ID NO: 13, and
 (ii) the heavy chain constant sequence of SEQ ID NO: 11. 
   
     
     
         28 . The method of  claim 24 , wherein the antigen binding protein is a human antibody, a humanized antibody, chimeric antibody, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a single chain antibody, a diabody, a triabody, a tetrabody, a Fab fragment, an F(fab′) 2  fragment, an IgD antibody, an IgE antibody, an IgM antibody, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, an IgG4 antibody, or an IgG4 antibody having at least one mutation in the hinge region. 
     
     
         29 . The method of  claim 24 , wherein the condition is diabetes, obesity, dyslipidemia, NASH, cardiovascular disease or metabolic syndrome. 
     
     
         30 . The method of  claim 29 , wherein the condition is type 2 diabetes.