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EP-4735016-A2 - INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN LIKE 1 (IGFBPL1) COMPOSITIONS AND METHODS OF USE THEREOF

EP4735016A2EP 4735016 A2EP4735016 A2EP 4735016A2EP-4735016-A2

Abstract

This disclosure relates to insulin-like growth factor binding protein like 1 (IGFBPL1) compositions and methods of use thereof, including inhibiting SORT1 and DCC activity expressed on neurons and microglia.

Inventors

  • LEVENSON, JONATHAN M.
  • BRYSON, JAMES W.
  • FURFINE, ERIC S.
  • KAZANTSEV, ALEXEI V.

Assignees

  • Firecyte Therapeutics, Inc.

Dates

Publication Date
20260506
Application Date
20240627

Claims (20)

  1. 1. A fusion protein comprising a half-life extending domain and a human IGFBPL1 (hIGFBPLI) polypeptide or a fragment thereof, wherein the half-life extending domain is operatively linked to the hIGFBPLI polypeptide or fragment thereof with or without a linker.
  2. 2. The fusion protein of claim 1, wherein the hIGFBPLI polypeptide or the fragment thereof comprises a thumb domain, an N-terminal domain, a Kazal domain, and Ig-like domain, a C-terminal domain, or any combination thereof.
  3. 3. The fusion protein of claim 2, wherein the thumb domain comprises the amino acid sequence of SEQ ID NO: 25, the N-terminal domain comprises the amino acid sequence of SEQ ID NO: 2, the Kazal domain comprises the amino acid sequence of SEQ ID NO: 27, the Ig-like domain comprises the amino acid sequence of SEQ ID NO: 26, and/or the C-terminal domain comprises the amino acid sequence of SEQ ID NO: 3.
  4. 4. The fusion protein of any one of claims 1-3, wherein the fragment of hIGFBPLI does not comprise the thumb domain of hIGFBPLI.
  5. 5. The fusion protein of any one of claims 1-4, wherein the fragment of hIGFBPLI does not comprise the N-terminal domain of hIGFBPLI.
  6. 6. The fusion protein of any one of claims 1-5, wherein the fragment of hIGFBPLI does not comprise the Kazal domain of hIGFBPLI.
  7. 7. The fusion protein of any one of claims 1-6, wherein the fragment of hIGFBPLI does not comprise the Ig-like domain of hIGFBPLI.
  8. 8. The fusion protein of any one of claims 1-7, wherein the fragment of hIGFBPLI does not comprise the C-terminal domain.
  9. 9. The fusion protein of any one of claims 1-3, wherein the fragment of hIGFBPLI comprises the N-terminal domain of hIGFBPLI, provided no other domain of hIGFBPLI is part of the hIGFBPLI fragment.
  10. 10. The fusion protein of claim 9, wherein the fragment of hIGFBPLI comprises the amino acid sequence selected from SEQ ID NOs: 2, 158, and 160-166.
  11. 11. The fusion protein of any one of claims 1-3, wherein the fragment of hIGFBPLI comprises the C-terminal domain of hIGFBPLI, provided no other domain of hIGFBPLI is part of the hIGFBPLI fragment.
  12. 12. The fusion protein of claim 11, wherein the fragment of hIGFBPLI comprises the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 179.
  13. 13. The fusion protein of any one of claims 1-3, wherein the fragment of hIGFBPLI comprises the thumb domain of hIGFBPLI, provided no other domain of hIGFBPLI is part of the hIGFBPLI fragment.
  14. 14. The fusion protein of claim 13, wherein the fragment of hIGFBPLI comprises the amino acid sequence of SEQ ID NO: 25.
  15. 15. The fusion protein of any one of claims 1-3, wherein the fragment of hIGFBPLI comprises the Ig-like domain of hIGFBPLI, provided no other domain of hIGFBPLI is part of the hIGFBPLI fragment.
  16. 16. The fusion protein of claim 15, wherein the fragment of hIGFBPLI comprises the amino acid sequence selected from SEQ ID Nos: 26, 167, and 169.
  17. 17. The fusion protein of any one of claims 1-3, wherein the fragment of hIGFBPLI comprises the Kazal domain of hIGFBPLI, provided no other domain of hIGFBPLI is part of the hIGFBPLI fragment.
  18. 18. The fusion protein of claim 17, wherein the fragment of hIGFBPLI comprises the amino acid sequence of SEQ ID NO: 27 or SEQ ID NO: 178.
  19. 19. The fusion protein of any one of claims 1-3, wherein the fragment of hIGFBPLI comprises the Ig-like domain and C-terminal domain of hIGFBPLI, provided no other domain of hIGFBPLI is part of the hIGFBPLI fragment.
  20. 20. The fusion protein of claim 19, wherein the fragment of hIGFBPLI comprises the amino acid sequence of SEQ ID NO: 168 or SEQ ID NO: 170.

Description

INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN LIKE 1 (IGFBPL1) COMPOSITIONS AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63/510,577, filed June 27, 2023, which is incorporated by reference herein in its entirety. BACKGROUND Insulin-like growth factor binding protein like 1 (IGFBPL1) is a multi-domain protein reported to have beneficial activity in neurodegenerative and neuroinflammatory conditions such as glaucoma by, for example, promoting neurite outgrowth. However, the underlying mechanisms and activities resulting in IGFBPL1 activity in such conditions are unknown. SUMMARY In some aspects, the disclosure provides a fusion protein comprising a half-life extending domain and a human IGFBPL1 (hIGFBPLI) polypeptide or a fragment thereof, wherein the half- life extending domain is operatively linked to the hIGFBPLI polypeptide or fragment thereof with or without a linker. In some aspects, the disclosure provides a fusion protein comprising a half-life extending domain and a means for binding DCC, wherein the half-life extending domain is operatively linked to the means with or without a linker. In some aspects, the disclosure provides a fusion protein comprising a half-life extending domain and a means for binding SORT1, wherein the half-life extending domain is operatively linked to the means with or without a linker. In some aspects, the disclosure provides a fusion protein comprising a half-life extending domain and a means for binding SORT1 and DCC, wherein the half-life extending domain is operatively linked to the means with or without a linker. In some embodiments, the hIGFBPLI polypeptide or the fragment thereof comprises a thumb domain, an N-terminal domain, a Kazal domain, and Ig-like domain, a C-terminal domain, or any combination thereof. In some embodiments, the thumb domain comprises the amino acid sequence of SEQ ID NO: 25, the N-terminal domain comprises the amino acid sequence of SEQ ID NO: 2, the Kazal domain comprises the amino acid sequence of SEQ ID NO: 27, the Ig-like domain comprises the amino acid sequence of SEQ ID NO: 26, and/or the C- terminal domain comprises the amino acid sequence of SEQ ID NO: 3. In some embodiments, the fragment of hIGFBPLI does not comprise the thumb domain of hIGFBPLI. In some embodiments, the fragment of hIGFBPLI does not comprise the N- terminal domain of hIGFBPLI. In some embodiments, the fragment of hIGFBPLI does not comprise the Kazal domain of hIGFBPLI. In some embodiments, the fragment of hIGFBPLI does not comprise the Ig-like domain of hIGFBPLI. In some embodiments, the fragment of hIGFBPLI does not comprise the C-terminal domain. In some embodiments, the fragment of hIGFBPLI comprises the N-terminal domain of hIGFBPLI, provided no other domain of hIGFBPLI is part of the hIGFBPLI fragment. In some embodiments, the fragment of hIGFBPLI comprises the amino acid sequence selected from SEQ ID NOs: 2, 158, and 160-166. In some embodiments, the fragment of hIGFBPLI comprises the C-terminal domain of hIGFBPLI, provided no other domain of hIGFBPLI is part of the hIGFBPLI fragment. In some embodiments, the fragment of hIGFBPLI comprises the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 179. In some embodiments, the fragment of hIGFBPLI comprises the thumb domain of hIGFBPLI, provided no other domain of hIGFBPLI is part of the hIGFBPLI fragment. In some embodiments, the fragment of hIGFBPLI comprises the amino acid sequence of SEQ ID NO: 25. In some embodiments, the fragment of hIGFBPLI comprises the Ig-like domain of hIGFBPLI, provided no other domain of hIGFBPLI is part of the hIGFBPLI fragment. In some embodiments, the fragment of hIGFBPLI comprises the amino acid sequence selected from SEQ ID Nos: 26, 167, and 169. In some embodiments, the fragment of hIGFBPLI comprises the Kazal domain of hIGFBPLI, provided no other domain of hIGFBPLI is part of the hIGFBPLI fragment. In some embodiments, the fragment of hIGFBPLI comprises the amino acid sequence of SEQ ID NO: 27 or SEQ ID NO: 178. In some embodiments, the fragment of hIGFBPLI comprises the Ig-like domain and C- terminal domain of hIGFBPLI, provided no other domain of hIGFBPLI is part of the hIGFBPLI fragment. In some embodiments, the fragment of hIGFBPLI comprises the amino acid sequence of SEQ ID NO: 168 or SEQ ID NO: 170. In some embodiments, the fragment of hIGFBPLI comprises the Kazal domain and the Ig-like domain of hIGFBPLI, provided no other domain of hIGFBPLI is part of the hIGFBPLI fragment. In some embodiments, the fragment of hIGFBPLI comprises the amino acid sequence of SEQ ID NO: 171 or SEQ ID NO: 173. In some embodiments, the fragment of hIGFBPLI comprises the Kazal domain, the Ig- like domain, and the C-terminal domain of hIGFBPLI, provided no other domain of hIGFBPLI is part of the hIGFBPLI fragment. In some embodiments, the fragment of hIGFBPLI comprises the amino acid sequence of SE