Histidyl-tRNA synthetase-Fc conjugates

Patent metadata

Field	Value
Publication number	US-9587235-B2
Application number	US-201414214491-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	Mar 7, 2017
Grant date	Mar 7, 2017

Abstract

The present invention provides histidyl-tRNA synthetase and Fc region conjugate polypeptides (HRS-Fc conjugates), such as HRS-Fc fusion polypeptides, compositions comprising the same, and methods of using such conjugates and compositions for treating or diagnosing a variety of conditions. The HRS-Fc conjugates of the invention have improved controlled release properties, stability, half-life, and other pharmacokinetic and biological properties relative to corresponding, unmodified HRS polypeptides.

First claim

The invention claimed is:

1. A histidyl-tRNA synthetase (HRS) fusion polypeptide, which consists essentially of an amino acid sequence at least 95% identical to SEQ ID NO:110.

2. The HRS fusion polypeptide of claim 1 , which consists of an amino acid sequence at least 97% identical to SEQ ID NO:110.

3. The HRS fusion polypeptide of claim 1 , which consists of an amino acid sequence at least 98% identical to SEQ ID NO:110.

4. The HRS fusion polypeptide of claim 3 , which consists of an amino acid sequence at least 99% identical to SEQ ID NO:110.

5. The HRS fusion polypeptide of claim 1 , where the HRS polypeptide comprises a WHEP domain.

6. The HRS fusion polypeptide of claim 1 , where the Fc region and the HRS polypeptide are separated by a peptide linker.

7. The HRS fusion polypeptide of claim 6 , where the peptide linker is about 1-10 amino acids, or about 1-5 amino acids in length.

8. The HRS fusion polypeptide of claim 6 , where the peptide linker is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 amino acids in length.

9. The HRS fusion polypeptide of claim 6 , where the peptide linker consists of Gly and/or Ser residues.

10. The HRS fusion polypeptide of claim 6 , where the peptide linker is a physiologically stable linker.

11. The HRS fusion polypeptide of claim 6 , where the peptide linker is a releasable linker, optionally an enzymatically-cleavable linker.

12. The HRS fusion polypeptide of claim 1 , which has altered pharmacokinetics relative to a corresponding unmodified HRS polypeptide.

13. The HRS fusion polypeptide of claim 12 , where said altered pharmacokinetics are increased serum half-life, increased bioavailability, exposure, and/or decreased clearance.

14. The HRS fusion polypeptide of claim 13 , wherein the HRS fusion polypeptide has a half life of at least 30 hours in mice.

15. The HRS fusion polypeptide of claim 1 , where the Fc region comprises a variant Fc region, relative to a wild-type Fc region.

16. The HRS fusion polypeptide of claim 15 , where the variant Fc region comprises a hybrid of one or more Fc regions from different human IgG subclasses.

17. The HRS fusion polypeptide of claim 15 , where the variant Fc region comprises a hybrid of one or more hinge, CH 2 , CH 3 , and/or CH 4 domains of Fc regions from different human IgG subclasses.

18. The HRS fusion polypeptide of claim 15 , where the variant Fc region is a modified glycoform, relative to a corresponding, wild-type Fc region.

19. The HRS fusion polypeptide of claim 15 , where the variant Fc region has altered pharmacokinetics relative to a corresponding, wild-type Fc region.

20. The HRS fusion polypeptide of claim 19 , where said altered pharmacokinetics include serum half-life, bioavailability, and/or clearance.

21. The HRS fusion polypeptide of claim 15 , where the variant Fc region has altered effector activity relative to a corresponding, wild-type Fc region.

22. The HRS fusion polypeptide of claim 21 , where said effector activity is one or more of complement activation, complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), or antibody-dependent cell-mediated phagocytosis (ADCP).

23. The HRS fusion polypeptide of claim 15 , where the variant Fc region has altered binding to one or more Fcγ receptors, relative to a corresponding, wild-type Fc region.

24. The HRS fusion polypeptide of claim 15 , where the variant Fc region has altered binding to one or more FcRn receptors, relative to a corresponding, wild-type Fc region.

25. The HRS fusion polypeptide of claim 15 , where the variant Fc region has altered solubility, relative to a corresponding, wild-type Fc region.

26. The HRS fusion polypeptide of claim 1 , which is substantially in dimeric form in a physiological solution.

27. The HRS fusion polypeptide of claim 1 , which has substantially the same secondary structure a corresponding unmodified HRS polypeptide, as determined via UV circular dichroism analysis.

28. The HRS fusion polypeptide of claim 1 , which has a plasma or sera pharmacokinetic AUC profile at least 5-fold greater than a corresponding, unmodified HRS polypeptide when administered to a mammal.

29. The histidyl-tRNA synthetase (HRS)-Fc fusion polypeptide of claim 1 , where the HRS-Fc fusion polypeptide has an anti-inflammatory activity.

30. A therapeutic composition, comprising a HRS fusion polypeptide of claim 1 and a pharmaceutically acceptable carrier or excipient, wherein the HRS fusion polypeptide as is at least about 95% pure and less than about 5% aggregated, and wherein the composition is substantially endotoxin-free.

Assignees

• Atyr Pharma Inc
• Atyr Pharma Inc

Inventors

• Buechler Ying
• Chiang Kyle
• Do Minh-Ha
• Lee Darin
• Piehl Kristi
• Thomas Marc
• Watkins Jeffry D
• Wu Chi-Fang
• Mendlein John D

Classifications

• C12N9/93 Primary

  Ligases (6) · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• C12N9/96

  Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C12Y601/01021

  Histidine-tRNA ligase (6.1.1.21) · CPC title