IP Library › Granted Patent US 12,358,963
Granted Patent B2
US 12,358,963 · App. 17/843,748 · Granted Jul 15, 2025

Regenerative polypeptides and uses thereof

Inventors: Hanadie Yousef (Redwood City, CA); Jeremy O'Connell (Palo Alto, CA); Thach Mai (South San Francisco, CA); Rami Jaafar (San Francisco, CA); Zhihua Li (San Jose, CA)
Assignee: Juvena Therapeutics, Inc.
C07K14/50A61K31/19A61K38/30A61P19/02A61P21/06
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Quick Facts
Patent No.
US 12,358,963
App. No.
17/843,748
Granted
Jul 15, 2025
Kind
B2
Abstract

Described herein are polypeptides comprising an FGF17, IGF2, or BMP? amino acid sequence and an amino acid sequence from a heterologous polypeptide useful for the treatment of soft-tissue and muscle diseases, disorders, and injuries. Also described herein are synergistic combinations of a Fibroblast Growth Factor Receptor agonist and a glycosaminoglycan, an Insulin-like Growth Factor 1 Receptor (IGF1R) agonist and a short chain fatty acid, and BMP receptor agonists and mTOR activators and/or glycosaminoglycans. Also described are methods of treating muscle and soft-tissue diseases comprising administering the polypeptides and/or synergistic compositions.

Claims (20)

1. A method of treating a muscle wasting disease or condition in an individual comprising administering to the individual a therapeutically effective amount of a polypeptide comprising an Insulin-like growth factor 2 (IGF-2) amino acid sequence and an N-terminal human serum albumin (HSA) heterologous polypeptide amino acid sequence, wherein the N-terminal HSA heterologous polypeptide amino acid sequence and the IGF2 amino acid sequence are separated by a flexible peptide linker, wherein the N-terminal HSA heterologous polypeptide amino acid sequence increases the stability or biological function of the IGF-2 amino acid sequence, and wherein the administering increases differentiation of myoblast cells by increasing fusion of myoblasts into multinucleated muscle fibers.

2. The method of claim 1 , wherein the muscle wasting disease or condition comprises a muscular dystrophy.

3. The method of claim 1 , further comprising the step of administering a short chain fatty acid.

4. The method of claim 3 , wherein the short chain fatty acid is a butyrate.

5. The method of claim 1 , wherein the IGF2 amino acid sequence comprises a human IGF2 amino acid sequence.

6. The method of claim 5 , wherein the human IGF2 amino acid sequence consists of an amino acid sequence at least about 98% identical to the amino acid sequence set forth in SEQ ID NO: 76.

7. The method of claim 5 , wherein the IGF2 sequence comprises at least one amino acid that is N-, C-, or O-linked glycosylated.

8. The method of claim 1 , wherein the N-terminal HSA heterologous polypeptide amino acid sequence comprises SEQ ID NO: 109, and wherein the flexible peptide linker comprises a glycine-serine linker or multimers of a glycine-serine linker.

9. The method of claim 8 , wherein the heterologous polypeptide amino acid sequence comprises a fragment of an immunoglobulin molecule and wherein the fragment of the immunoglobulin molecule comprises the hinge domain of an IgG, the CH2 domain of an IgG, the CH3 domain of an IgG, or any combination thereof.

10. The method of claim 9 , wherein the fragment of the immunoglobulin molecule comprises one or more mutations that reduce the effector function of the fragment of the immunoglobulin molecule.

11. The method of claim 10 , wherein the fragment of the immunoglobulin molecule comprises a fragment of an IgG4 molecule.

12. The method of claim 11 , wherein the fragment of the immunoglobulin molecule comprises a fragment of an IgG4 molecule with at least one of the following amino acid mutations or sets of mutations in the fragment of the immunoglobulin molecule: N434A, N434H, T307A/E380A/N434A, M252Y/S254T/T256E, 433K/434F/436H, T250Q, T250F, M428L, M428F, T250Q/M428L, N434S, V308W, V308Y, V308F, M252Y/M428L, D2591/V308F, M428L/V308F, Q311V/N434S, T307Q/N434A, E258F/V427T, S228P, L235E, S228P/L235E/R409K, S228P/L235E, K370Q, K370E, deletion of G446, deletion of K447, and combinations thereof of IgG4 according to the EU numbering system.

13. The method of claim 1 , further comprising the step of increasing a regenerative capability of myoblast cells in the subject by administering the polypeptide according to a dosage schedule, wherein the dosage schedule comprises repeated administrations of the therapeutically effective amount of the polypeptide to the subject.

14. The method of claim 13 , wherein the regenerative capability is a proliferation of the myoblast cells, a degree of differentiation of the myoblast cells, or a cellular survival of the myoblast cells.

15. The method of claim 14 , wherein increasing a proliferation of the myoblast cells produces an increase in new myofibers.

16. The method of claim 14 , wherein the subject has an increase in a muscle regeneration.

17. The method of claim 13 , wherein a grip strength of the subject is increased.

18. The method of claim 13 , wherein a weight of muscle in the subject is increased.

19. The method of claim 13 , wherein a lean body mass of the subject is increased.

20. The method of claim 13 , wherein an appendicular skeletal muscle index of the subject is increased.

Continuity (4)
Provisional Application 62953431 · Dec 24, 2019
Provisional Application 62953429 · Dec 24, 2019
Provisional Application 62953427 · Dec 24, 2019
Related Publication 20230398187A1 · Dec 14, 2023
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