FGF-18 truncated variants having increased receptor specificity and uses thereof
Inventors
Yayon, Avner • Rom, Eran • Sirkis, Roy • Strauss-Ayali, Dalit
Assignees
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Publication Number
US-9226949-B2
Publication Date
2016-01-05
Expiration Date
Abstract
The present invention relates to fibroblast growth factor 18 (FGF-18) variants having various truncations beyond the signal peptide domain of the N-terminus, which activate FGFR3 with increased specificity. The invention further relates to polynucleotides encoding the variants, pharmaceutical compositions comprising same and methods for use thereof in treating cartilage and skeletal disorders.
Core Innovation
The invention relates to isolated FGF-18 polypeptides that are N-terminally truncated by 50 amino acids and include a substitution at position Gln51, wherein Gln51 is replaced by a Met residue. The isolated FGF-18 polypeptides comprise an amino acid sequence selected from the group consisting of SEQ ID NO: 47, SEQ ID NO: 67, and SEQ ID NO: 69, and exhibit increased receptor selectivity when compared to an isolated wild-type FGF-18 polypeptide.
In particular, the engineered FGF-18 polypeptides are described as having a gain of activity by at least a factor of two toward FGFR3 but not toward all FGFR subtypes. The document further describes additional selectivity-improving changes involving a substitution at Leu52, where Leu52 is replaced by an amino acid residue other than leucine, with variants comprising sequences selected from SEQ ID NO: 67 and SEQ ID NO: 69.
The background problem addressed by the invention is that receptor activation by FGF-18 variants can lack the desired receptor selectivity, and activity toward FGFR subtypes other than FGFR3 is not sufficiently eliminated. The described FGF-18 variants solve this by increasing receptor selectivity toward FGFR3 while largely eliminating activation toward other FGFR subtypes, with the goal of improved functional activity in cartilage contexts.
The document ties the FGFR3-selective polypeptides to pharmaceutical compositions for cartilage repair and degenerative joint disease treatment. The compositions are described as comprising at least one isolated FGF-18 polypeptide variant, and the document further describes optional co-administration with hyaluronic acid or C-type natriuretic peptide (CNP) for synergy.
Claims Coverage
The independent claims cover four core categories: isolated FGF-18 polypeptides with defined N-terminal truncation and amino-acid substitutions, pharmaceutical compositions containing those polypeptides, pharmaceutical compositions containing polynucleotides encoding those polypeptides, and additional polypeptide variants with a non-leucine substitution at Leu52. The inventive features are defined by the same functional selectivity criterion and by specific sequence/encoding selections.
FGF-18 polypeptide with 50-amino-acid N-terminal truncation and Gln51→Met substitution for FGFR3-selective activity
An isolated FGF-18 polypeptide having a 50 amino acid N-terminal truncation with the Gln51 replaced by a Met residue, comprising an amino acid sequence selected from SEQ ID NO: 47, SEQ ID NO: 67, and SEQ ID NO: 69, and having increased receptor selectivity versus isolated wild-type FGF-18 by a gain of activity by at least a factor of two toward FGFR3 but not toward all FGFR subtypes.
FGF-18 pharmaceutical composition with FGFR3-selective truncated Gln51→Met variants
A pharmaceutical composition comprising as an active ingredient at least one isolated FGF-18 polypeptide having a 50 amino acid N-terminal truncation with the Gln51 replaced by a Met residue, the polypeptide comprising an amino acid sequence selected from SEQ ID NO: 47, SEQ ID NO: 67, and SEQ ID NO: 69, and having increased receptor selectivity versus isolated wild-type FGF-18 by a gain of activity by at least a factor of two toward FGFR3 but not toward all FGFR subtypes.
Polynucleotide-encoded FGFR3-selective truncated FGF-18 variants
A pharmaceutical composition comprising as an active ingredient at least one isolated polynucleotide encoding an FGF-18 polypeptide having a 50 amino acid N-terminal truncation with the Gln51 replaced by a Met residue, the polypeptide comprising an amino acid sequence selected from SEQ ID NO: 47, SEQ ID NO: 67, and SEQ ID NO: 69, and having increased receptor selectivity versus isolated wild-type FGF-18 by a gain of activity by at least a factor of two toward FGFR3 but not toward all FGFR subtypes.
FGF-18 polypeptide with non-leucine Leu52 substitution for FGFR3-selective activity
An isolated FGF-18 polypeptide having a 50 amino acid N-terminal truncation with the Gln51 replaced by a Met residue and the Leu52 replaced by an amino acid residue other than leucine, comprising an amino acid sequence selected from SEQ ID NO: 67 and SEQ ID NO: 69, and having increased receptor selectivity versus isolated wild-type FGF-18 by a gain of activity by at least a factor of two toward FGFR3 but not toward all FGFR subtypes.
Across the independent claims, the patent defines specific isolated FGF-18 polypeptides and polynucleotide-encoded equivalents via 50 amino acid N-terminal truncation plus Gln51→Met, with additional restriction variants involving Leu52 substitution to a non-leucine residue. In all independent claim categories, the functional requirement is increased receptor selectivity versus wild-type FGF-18, defined as at least a two-fold gain of activity toward FGFR3 but not toward all FGFR subtypes.
Stated Advantages
Increased receptor selectivity toward FGFR3 compared to isolated wild-type FGF-18.
A gain of activity by at least a factor of two toward FGFR3 but not toward all FGFR subtypes.
Documented Applications
Cartilage repair by administering a pharmaceutical composition comprising the isolated FGF-18 polypeptide variants.
Treatment of degenerative joint disease, including osteoarthritis, via administration of the pharmaceutical composition.
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