Fusion polypeptides and methods of use

Abstract

The present disclosure relates to fusion polypeptides comprising fragments from a first and a second FGF family member, nucleic acids encoding the fusion polypeptides, vectors and host cells containing the same, and methods of making and using such compositions in the treatment of FGF-related diseases, disorders, and conditions.

1 - 57 . (canceled) 
     
     
         58 . A fusion polypeptide, comprising a structure of formula (I):
   (S1)-(β1)-(S2)-(β2)-(S3)-(β3)-(S4)-(β4)-(S5)-(β5)-(S6)-(β6)-(S7)-(β7)-(S8)-(β8)-(S9)-(β9)-(S10)-(β10)-(S11)-(β11)-(S12)-(β12)-(S13)  (I),
   wherein:   β2 comprises an amino acid sequence exhibiting at least 90% homology to a fragment having residues from about I39 to G43 of FGF18 (SEQ ID NO:1) or from about V44 to G48 of FGF17 (SEQ ID NO:2);   β3 comprises an amino acid sequence exhibiting at least 90% homology to a fragment having residues from about R45 to A48 of FGF18 (SEQ ID NO:1) or from about R50 to A53 of FGF17 (SEQ ID NO:2);   β5 comprises an amino acid sequence exhibiting at least 90% homology to a fragment having residues from about Q69 to K75 of FGF18 (SEQ ID NO:1) or from about R74 to A80 of FGF17 (SEQ ID NO:2);   β6 comprises an amino acid sequence exhibiting at least 90% homology to a fragment having residues from about F79 to L81 of FGF18 (SEQ ID NO:1) or from about K84 to 186 of FGF17 (SEQ ID NO:2);   β7 comprises an amino acid sequence exhibiting at least 90% homology to a fragment having residues from about K88 to G91 of FGF18 (SEQ ID NO:1) or from about K93 to G96 of FGF17 (SEQ ID NO:2);   β8 comprises an amino acid sequence exhibiting at least 90% homology to a fragment having residues from about V101 to K105 of FGF18 (SEQ ID NO:1) or from about V106 to I110 of FGF17 (SEQ ID NO:2);   β10 comprises an amino acid sequence exhibiting at least 90% homology to a fragment having residues from about G121 to V124 of FGF18 (SEQ ID NO:1) or from about G126 to M129 of FGF17 (SEQ ID NO:2);   β11 comprises an amino acid sequence exhibiting at least 90% homology to a fragment having residues from about K134 to T138 of FGF18 (SEQ ID NO:1) or from about Q139 to S143 of FGF17 (SEQ ID NO:2); and   each of S1, S2, S3, S4, S5, S6, S7, S8, S9, S10, S11, S12, and S13 is independently a spacer sequence having between 1 to about 50 amino acid residues.   
     
     
         59 . The fusion polypeptide of  claim 58 , wherein β1 is identical to a fragment having residues from about Q24 to Y31 of FGF18 (SEQ ID NO: 1). 
     
     
         60 . The fusion polypeptide of  claim 58 , wherein β1 is identical to a fragment having residues from about Q29 to Y36 of FGF17 (SEQ ID NO: 2). 
     
     
         61 . The fusion polypeptide of  claim 58 , wherein β4 is identical to a fragment having residues from about Q58 to T63 of FGF18 (SEQ ID NO: 1). 
     
     
         62 . The fusion polypeptide of  claim 58 , wherein β4 is identical to a fragment having residues from about T68 of FGF17 (SEQ ID NO: 2). 
     
     
         63 . The fusion polypeptide of  claim 58 , wherein (39 is identical to a fragment having residues from about Y111 to A117 of FGF18 (SEQ ID NO: 1). 
     
     
         64 . The fusion polypeptide of  claim 58 , wherein (39 is identical to a fragment having residues from about Y116 to A122 of FGF17 (SEQ ID NO: 2). 
     
     
         65 . The fusion polypeptide of  claim 58 , wherein (312 is identical to a fragment having residues from about H146 to R150 of FGF18 (SEQ ID NO: 1). 
     
     
         66 . The fusion polypeptide of  claim 58 , wherein (312 is identical to a fragment having residues from about H151 to R155 of FGF17 (SEQ ID NO: 2). 
     
     
         67 . The fusion polypeptide of  claim 58 , wherein the fusion polypeptide comprises at least 90% sequence homology to FGF18 (SEQ ID NO:1) or FGF17 (SEQ ID NO:2). 
     
     
         68 . The fusion polypeptide of  claim 58 , wherein the fusion polypeptide comprises at least 95% sequence homology to FGF18 (SEQ ID NO:1) or FGF17 (SEQ ID NO:2). 
     
     
         69 . The fusion polypeptide of  claim 58 , wherein the fusion polypeptide comprises the secondary structure of said FGF18 (SEQ ID NO:1) or said FGF17 (SEQ ID NO:2). 
     
     
         70 . The fusion polypeptide of  claim 58 , wherein the fusion polypeptide comprises a first fragment from FGF18 (SEQ ID NO:1) and a second fragment from FGF17 (SEQ ID NO:2), wherein said first and second fragments are fused together at a fusion site, wherein the fusion site comprises a sequence of at least 6 amino acids that is homology to a corresponding sequence in said FGF18 (SEQ ID NO:1) and said FGF17 (SEQ ID NO:2). 
     
     
         71 . The fusion polypeptide of  claim 58 , wherein a N-terminus of said fusion polypeptide is further modified by a polyethylene glycol (PEG). 
     
     
         72 . The fusion polypeptide of  claim 58 , wherein the fusion polypeptide is devoid of any additional T-epitope or B-epitope as compared to that of said FGF18 (SEQ ID NO:1) or said FGF17 (SEQ ID NO:2). 
     
     
         73 . A pharmaceutical composition comprising the fusion polypeptide of  claim 58  and a pharmaceutically acceptable excipient. 
     
     
         74 . A pharmaceutical composition comprising the fusion polypeptide of  claim 71  and a pharmaceutically acceptable excipient. 
     
     
         75 . A host cell expressing the fusion polypeptide of  claim 58 . 
     
     
         76 . A vector comprising a polynucleotide that encodes the fusion polypeptide of  claim 58 . 
     
     
         77 . A method for producing a fusion polypeptide, comprising expressing a vector that comprises a polynucleotide encoding the fusion polypeptide of  claim 58  in a cell under conditions suitable for protein expression, thereby producing said fusion polypeptide.