Compositions for increasing half-life of a therapeutic agent in canines and methods of use

Abstract

Provided are compositions for increasing the half-life of a polypeptide or polypeptides in a canine and methods of their use. The compositions involve variant canine IgG Fc regions.

1 .- 30 . (canceled) 
     
     
         31 . A polypeptide comprising a canine IgG Fc region variant, or a canine FcRn-binding region thereof, wherein the canine IgG Fc region variant, or the canine FcRn-binding region thereof, comprises an amino acid substitution at a position that corresponds to amino acid position 426 of a wild type canine IgG, wherein the amino acid position is based on EU numbering, wherein the polypeptide has increased binding affinity to canine FcRn when compared to an Fc domain of the wild type canine IgG, and wherein the wild type canine IgG is a canine IgG.B comprising an Fc domain having the amino acid sequence of SEQ ID NO: 10. 
     
     
         32 . The polypeptide of  claim 31 , wherein the amino acid substitution at the position that corresponds to amino acid position 426 of a wild type canine IgG is A426Y, A426H, or A426F. 
     
     
         33 . The polypeptide of  claim 32 , wherein the amino acid substitution at the position that corresponds to amino acid position 426 of a wild type canine IgG is A426Y. 
     
     
         34 . The polypeptide of  claim 32 , wherein the amino acid substitution at the position that corresponds to amino acid position 426 of a wild type canine IgG is A426H. 
     
     
         35 . The polypeptide of  claim 32 , wherein the amino acid substitution at the position that corresponds to amino acid position 426 of a wild type canine IgG is A426F. 
     
     
         36 . The polypeptide of  claim 31 , wherein the canine IgG Fc region variant, or the canine FcRn-binding region thereof, further comprises an amino acid substitution at a position that corresponds to amino acid position 286 of a wild type canine IgG. 
     
     
         37 . The polypeptide of  claim 36 , wherein the amino acid substitution at the position that corresponds to amino acid position 286 of a wild type canine IgG is T286F, T286W, T286L, or T286Y. 
     
     
         38 . The polypeptide of  claim 37 , wherein the amino acid substitution at the position that corresponds to amino acid position 286 of a wild type canine IgG is T286F. 
     
     
         39 . The polypeptide of  claim 37 , wherein the amino acid substitution at the position that corresponds to amino acid position 286 of a wild type canine IgG is T286W. 
     
     
         40 . The polypeptide of  claim 37 , wherein the canine IgG Fc region variant, or the canine FcRn-binding region thereof, comprises amino acid substitutions selected from the group consisting of:
 (a) A426Y and T286F;   (b) A426Y and T286W;   (c) A426Y and T286L;   (d) A426Y and T286Y;   (e) A426H and T286F;   (f) A426H and T286W;   (g) A426H and T286L;   (h) A426H and T286Y;   (i) A426F and T286F;   (j) A426F and T286W;   (k) A426F and T286L; and   (l) A426F and T286Y.   
     
     
         41 . The polypeptide of  claim 37 , wherein the canine IgG Fc region variant, or the canine FcRn-binding region thereof, comprises amino acid substitutions A426Y in combination with T286F or T286W. 
     
     
         42 . The polypeptide of  claim 37 , wherein the canine IgG Fc region variant, or the canine FcRn-binding region thereof, comprises amino acid substitutions A426H in combination with T286F or T286W. 
     
     
         43 . The polypeptide of  claim 31 , wherein the polypeptide binds to a canine FcRn at a higher level at an acidic pH than at a neutral pH in a binding assay. 
     
     
         44 . The polypeptide of  claim 31 , further comprising a binding domain comprising (i) six complementarity determining regions (CDRs) of an immunoglobulin molecule; (ii) a ligand binding domain of a canine receptor protein, (iii) a nanobody, or (iv) an extracellular domain of a canine receptor protein. 
     
     
         45 . A fusion molecule comprising the polypeptide of  claim 31  and a polypeptide selected from the group consisting of EPO, CTLA4, LFA3, VEGFR1/VEGFR3, IL-1R, IL-4R, GLP-1 receptor agonist, and Thrombopoietin binding peptide. 
     
     
         46 . A pharmaceutical composition comprising (i) the polypeptide of  claim 31 , and (ii) a pharmaceutically acceptable excipient. 
     
     
         47 . A polypeptide comprising a canine IgG Fc region variant, or a canine FcRn-binding region thereof, wherein the canine IgG Fc region variant, or the canine FcRn-binding region thereof, comprises amino acid substitutions selected from the group consisting of A426F in combination with one or more of (i) T286F, T286W, T286L, or T286Y; (ii) D312P; (iii) N434R; and (iv) Y436H; wherein the amino acid positions are based on EU numbering, wherein the polypeptide has increased binding affinity to canine FcRn when compared to an Fc domain of a wild type canine IgG, and wherein the wild type canine IgG is a canine IgG.B comprising an Fc domain having the amino acid sequence of SEQ ID NO: 10.