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US 8,273,358 B2Granted
Activatable clostridial toxins
AssigneeAllergan, Inc.
InventorsLance E. Steward, Joseph Francis, Ester Fernandez-Salas, Sanjiv Ghanshani, Marcella A. Gilmore, Shengwen Li, J. Oliver Dolly, Kei Roger Aoki
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Abstract
Compositions comprising activatable recombinant neurotoxins and polypeptides derived therefrom. The invention also comprises nucleic acids encoding such polypeptides, and methods of making such polypeptides and nucleic acids.
Claims9
A recombinant single-chain polypeptide comprising:
- a) a first amino acid sequence region comprising
- i) a first domain comprising a binding element comprising an opioid peptide able to preferentially interact with an opioid peptide receptor under physiological conditions;
- and
- ii) a second domain comprising a translocation element comprising a Clostridial neurotoxin translocation domain able to facilitate the transfer of a Clostridial toxin light chain across a vesicular membrane;
- b) a second amino acid sequence region comprising a therapeutic element comprising a Clostridial neurotoxin light chain having biological activity when released into the cytoplasm of said target cell;
- and
- c) a third amino acid sequence region comprising an exogenous protease cleavage site;
- wherein said first and second amino acid sequence regions are separated by said third amino acid sequence region, wherein said exogenous protease cleavage site comprises a tobacco vein mottling virus protease cleavage site selected from the group consisting of:
- SEQ ID NO:
- 132, SEQ ID NO:
- 133, SEQ ID NO:
- 134, SEQ ID NO:
- 135, SEQ ID NO:
- 136, and SEQ ID NO:
- 137.
12 more elements
A recombinant single-chain polypeptide comprising:
- a) a first amino acid sequence region comprising
- i) a first domain comprising a binding element comprising an opioid peptide able to preferentially interact with an opioid peptide receptor under physiological conditions;
- and
- ii) a second domain comprising a translocation element comprising a Clostridial neurotoxin translocation domain able to facilitate the transfer of a Clostridial toxin light chain across a vesicular membrane;
- b) a second amino acid sequence region comprising a therapeutic element comprising a Clostridial neurotoxin light chain having biological activity when released into the cytoplasm of said target cell;
- and
- c) a third amino acid sequence region comprising an exogenous protease cleavage site;
- wherein said first and second amino acid sequence regions are separated by said third amino acid sequence region, wherein said exogenous protease cleavage site comprises a subtilisin cleavage site selected from the group consisting of:
- SEQ ID NO:
- 41, SEQ ID NO:
- 42, SEQ ID NO:
- 43, SEQ ID NO:
- 44, and SEQ ID NO:
- 45.
11 more elements
A recombinant single-chain polypeptide comprising:
- a) a first amino acid sequence region comprising
- i) a first domain comprising a binding element comprising an opioid peptide able to preferentially interact with an opioid peptide receptor under physiological conditions;
- and
- ii) a second domain comprising a translocation element comprising a Clostridial neurotoxin translocation domain able to facilitate the transfer of a Clostridial toxin light chain across a vesicular membrane;
- b) a second amino acid sequence region comprising a therapeutic element comprising a Clostridial neurotoxin light chain having biological activity when released into the cytoplasm of said target cell;
- and
- c) a third amino acid sequence region comprising an exogenous protease cleavage site;
- wherein said first and second amino acid sequence regions are separated by said third amino acid sequence region, wherein said exogenous protease cleavage site comprises a non-human Caspase 3 protease cleavage site selected from the group consisting of:
- SEQ ID NO:
- 139, SEQ ID NO:
- 140, SEQ ID NO:
- 141, SEQ ID NO:
- 142, SEQ ID NO:
- 143 and SEQ ID NO:
- 144.
12 more elements
Dependencies are inferred from the claim text.