Engineered fibroblast growth factor 1 variants with increased proteolytic stability
View Patent ↗The present invention provides methods of screening for proteolytically stable growth factor variants, including, for example variants of human fibroblast growth factor 1 (FGF1) The present invention also provides for FGF1 variants comprising at least one amino acid substitution, an amino acid deletion, an amino acid addition and combinations thereof, wherein the resulting FGF1 variant exhibits increased proteolytic stability as compared to wild-type FGF1, as well as related uses.
1 . A variant of human fibroblast growth factor 1 (FGF1) of SEQ ID NO:1 comprising the amino acid substitution L131R, wherein the resulting FGF1 variant exhibits increased proteolytic stability as compared to wild-type FGF1 of SEQ ID NO:1, wherein said FGF1 variant is a fibroblast growth factor receptor (FGFR) antagonist.
2 . The variant according to claim 1 , wherein said FGF1 variant further comprises at least one amino acid substitution selected from the group consisting of D28N, Q40P, S47I, and H93G.
3 . The variant according to claim 1 , wherein said variant further comprises amino acid substitution D28N.
4 . The variant according to claim 1 , wherein said FGF1 variant further comprises amino acid substitutions Q40P, S47I, and H93G.
5 . The variant according to claim 1 , wherein said FGF1 variant further comprises amino acid substitutions D28N, Q40P, S47I, and H93G.
6 . The variant according to claim 1 , wherein said FGF1 variant is conjugated to a member selected from a detectable moiety, a water-soluble polymer, a water-insoluble polymer, a therapeutic moiety, a targeting moiety and a combination thereof.
7 . The variant according to claim 6 , wherein said FGF1 variant is conjugated to a detectable moiety selected from a radioisotope, a paramagnet, a fluorophore and combinations thereof.
8 . The variant according to claim 6 , wherein said FGF1 variant is conjugated to a detectable moiety to form a diagnostic imaging agent.
9 . A pharmaceutical formulation comprising a FGF1 variant according to claim 1 , wherein said variant is in combination with a pharmaceutically acceptable carrier.