Modified Clostridial toxins with enhanced targeting capabilities for endogenous Clostridial toxin receptor systems
The specification discloses modified Clostridial toxins comprising a Clostridial toxin enzymatic domain, a Clostridial toxin translocation domain and an enhanced Clostridial toxin binding domain; polynucleotide molecules encoding such modified Clostridial toxins; and method of producing such modified Clostridial toxins.
1. A modified di-chain Clostridial toxin comprising:
a) a first chain comprising a Clostridial toxin enzymatic domain that executes an enzymatic target modification step of a Clostridial toxin intoxication process; and,
b) a second chain comprising a Clostridial toxin translocation domain that executes a translocation step of a Clostridial toxin intoxication process and
an enhanced targeting domain comprising a Fibroblast Growth Factor (FGF) β-trefoil domain that selectively binds a Fibroblast Growth Factor Receptor-3 (FGFR3);
wherein the modification is a substitution of a Clostridial toxin β-trefoil domain with the Fibroblast Growth Factor (FGF) β-trefoil domain; and
wherein the modified Clostridial toxin exhibits enhanced binding activity for an endogenous Clostridial toxin receptor system relative to the binding activity of a Clostridial toxin without the modification.
2. A polynucleotide molecule encoding the modified Clostridial toxin according to claim 1 .
3. An expression vector comprising the polynucleotide molecule according to claim 2 .