Clostridial Neurotoxins Comprising an Activating Endosomal Protease Cleavage Site
OwnerSai Man LIU, Karen BUNTINGinventors
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Abstract
The present invention relates to clostridial neurotoxins engineered to comprise an endosomal protease cleavage site within the activation loop, wherein cleavage at said site produces an active di-chain clostridial neurotoxin. The invention also relates to methods for manufacturing the same, as well as related pharmaceutical compositions, nucleotide sequences, and therapeutic and cosmetic uses. The invention further relates to a method for proteolytically processing said single-chain clostridial neurotoxins into a corresponding di-chain clostridial neurotoxin.
Claims29
An engineered clostridial neurotoxin, comprising an endosomal protease cleavage site, wherein cleavage at said cleavage site results in the production of a di-chain form of the engineered clostridial neurotoxin, and
- wherein the endosomal protease cleavage site is a cleavage site specific for:
- (a) asparagine endopeptidase (AEP);
- or
- (b) a cathepsin, optionally cathepsin L1, B, D, K or S.
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An engineered clostridial neurotoxin comprising an endosomal protease cleavage site, which comprises a polypeptide sequence having at least 70% sequence identity, at least 80%, at least 90%, or at least 95% sequence identity to SEQ ID NO:
- 160-162.
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A method for proteolytically processing a single-chain clostridial neurotoxin into a corresponding di-chain clostridial neurotoxin, the method comprising:
- (a) providing a single-chain clostridial neurotoxin;
- and
- (b) contacting the single-chain clostridial neurotoxin with an endosomal protease;
- wherein the single-chain clostridial neurotoxin has an activation loop, wherein the endosomal protease hydrolyses a peptide bond of the activation loop thereby producing a di-chain clostridial neurotoxin.
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Dependencies are inferred from the claim text.