Neurotoxins exhibiting shortened biological activity

Patent metadata

Field	Value
Publication number	US-2017072030-A1
Application number	US-201615342376-A
Country	US
Kind code	A1
Filing date	Nov 3, 2016
Priority date	Jul 2, 2009
Publication date	Mar 16, 2017
Grant date	—

Abstract

The present invention relates to the pharmaceutical field. Specifically, it contemplates a polynucleotide encoding a Neurotoxin polypeptide exhibiting a reduced duration of biological effect in a subject, wherein the polypeptide comprises at feast one degradation signal in the light chain as well as vectors and host calls comprising the polynucleotide, polypeptides encoded thereby and antibodies specifically binding to the polypeptides. Moreover, the invention relates to medicaments comprising the polynucleotides and polypeptides as well as specific therapeutic applications thereof. Furthermore, the present invention contemplates methods for the manufacture of the polypeptides and medicaments.

First claim

1 . A method of weakening muscle strength and contraction for facilitating wound healing, immobilization for bone and tendon fracture treatment, post surgery immobilization, immobilization in connection with haemorrhoidectomy, immobilization in connection with introduction of dental implants, immobilization in connection with hip joint replacement (endoprothesis), immobilization in connection with knee arthroplasty, immobilization in connection with ophthalmological surgery, acne, or irritable bowel disease in a subject in need thereof, comprising a step of administering to the subject a therapeutically effective amount of a modified neurotoxin polypeptide comprising at least one degradation signal in a light chain of the neurotoxin polypeptide which exhibits a reduced duration of a biological effect.

2 . The method of claim 1 , wherein the modified neurotoxin polypeptide is administered In an amount which is therapeutically effective for weakening muscle strength and contraction in a subject following hip joint replacement surgery.

3 . The method of claim 1 , wherein the modified neurotoxin polypeptide is administered in an amount which is therapeutically effective for weakening muscle strength and contraction in a subject following Knee arthroplasty.

4 . The method of claim 1 , wherein the modified neurotoxin polypeptide exhibits a reduced duration of the biological effect in a subject in comparison to the biological effect of an unmodified neurotoxin polypeptide in a subject.

5 . The method of claim 1 , wherein the modified neurotoxin polypeptide is administered in an amount which is therapeutically effective to cause muscle paralysis in the subject.

6 . The method of claim 1 , wherein the reduced duration of the biological effect in a subject persists less than 4, 3 or 2 weeks.

7 . The method of claim 1 , wherein the modified neurotoxin polypeptide comprises a modified form of a wild-type neurotoxin light chain, wherein a wild-type neurotoxin comprises the amino acid sequence of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14 or 16.

8 . The method of claim 1 , wherein the at least one degradation signal in the light chain is selected from:
a) at least one internally or terminally introduced PEST motif; b) at least one internally or terminally introduced E3 ligase recognition motif; c) an N-terminal oligo-lysine residue; d) an N-terminally linked ubiquitin; e) a substitution of the N-terminal proline with a basic amino acid; f) substitutions of surface displayed amino acid residues with lysine; and g) a substitution of the N-terminal proline with a basic amino acid in combination with substitutions of surface displayed amino acid residues with lysine.

Assignees

• Merz Pharma Gmbh & Co Kgaa

Inventors

• Hofmann Fred
• FREVERT Jürgen

Classifications

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• A61P41/00

  Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61K38/4893 Primary

  Botulinum neurotoxin (3.4.24.69) · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title