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CN-121985965-A - Combination therapy of ActRIIB receptor variants and GLP-1 agonists

CN121985965ACN 121985965 ACN121985965 ACN 121985965ACN-121985965-A

Abstract

The present disclosure provides combinations of tgfβ superfamily ligand binding agents and GLP-1 agonists, compositions thereof, and methods for treating metabolic disorders.

Inventors

  • Julia Schulman
  • Thomas. P. Loisel
  • GILLES TREMBLAY
  • Morin O'Connor McCotter
  • Wanna Kanbadi K. Kanas
  • Gautier Sichang
  • Michael J. Littler
  • Ilya A. Jihomilov

Assignees

  • 35制药有限公司

Dates

Publication Date
20260505
Application Date
20240906
Priority Date
20230908

Claims (20)

  1. 1. A combination, which comprises (A) A tgfβ superfamily ligand binding agent comprising a first polypeptide and a second polypeptide, wherein the first polypeptide and the second polypeptide each comprise: i. A polypeptide comprising an amino acid sequence that is at least 90% identical to an ActRIIB type receptor (ActRIIB) extracellular domain (ECD) variant, the ActRIIB ECD variant comprising an amino acid substitution at a position corresponding to position 33 of SEQ ID No. 2; Fc domain monomer, and A peptide linker linking said polypeptide to said Fc domain monomer, and (B) Glucagon-like peptide-1 (GLP-1) agonists.
  2. 2. The combination of claim 1, wherein the ActRIIB ECD variant exhibits reduced inhibition of BMP-9 and/or BMP-10 compared to a wild type ActRIIB extracellular domain.
  3. 3. The combination of claim 1 or claim 2, wherein the amino acid substitution is selected from L33F, L33Q, L33Y, L33W, L33H, L33R, L33E, L K and L33M.
  4. 4. The combination of any one of claims 1-3, wherein the ActRIIB ECD variant comprises the amino acid substitution L33F.
  5. 5. The combination of claim 4, wherein the ActRIIB ECD variant (A) Comprising an amino acid sequence which is at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO. 10, or (B) Comprising or consisting of the amino acid sequence of SEQ ID NO. 10.
  6. 6. The combination of any one of claims 1-3, wherein the ActRIIB ECD variant comprises the amino acid substitution L33Q.
  7. 7. The combination of claim 6, wherein the ActRIIB ECD variant (A) Comprising an amino acid sequence which is at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO. 11, or (B) Comprising or consisting of the amino acid sequence of SEQ ID NO. 11.
  8. 8. The combination of any one of claims 1-3, wherein the ActRIIB ECD variant comprises the amino acid substitution L33Y.
  9. 9. The combination of claim 8, wherein the ActRIIB ECD variant (A) Comprising an amino acid sequence which is at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO. 12, or (B) Comprising or consisting of the amino acid sequence of SEQ ID NO. 12.
  10. 10. The combination of any one of claims 1-3, wherein the ActRIIB ECD variant comprises the amino acid substitution L33W.
  11. 11. The combination of claim 10, wherein the ActRIIB ECD variant (A) Comprising an amino acid sequence which is at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO. 13, or (B) Comprising or consisting of the amino acid sequence of SEQ ID NO. 13.
  12. 12. The combination of any one of claims 1-3, wherein the ActRIIB ECD variant comprises the amino acid substitution L33H.
  13. 13. The combination of claim 12, wherein the ActRIIB ECD variant (A) Comprising an amino acid sequence which is at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO. 14, or (B) Comprising or consisting of the amino acid sequence of SEQ ID NO. 14.
  14. 14. The combination of any one of claims 1-3, wherein the ActRIIB ECD variant comprises the amino acid substitution L33R.
  15. 15. The combination of claim 14, wherein the ActRIIB ECD variant (A) Comprising an amino acid sequence which is at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO. 15, or (B) Comprising or consisting of the amino acid sequence of SEQ ID NO. 15.
  16. 16. The combination of any one of claims 1-3, wherein the ActRIIB ECD variant comprises the amino acid substitution L33E.
  17. 17. The combination of claim 16, wherein the ActRIIB ECD variant (A) Comprising an amino acid sequence which is at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO. 16, or (B) Comprising or consisting of the amino acid sequence of SEQ ID NO. 16.
  18. 18. The combination of any one of claims 1-3, wherein the ActRIIB ECD variant comprises the amino acid substitution L33K.
  19. 19. The combination of claim 18, wherein the ActRIIB ECD variant (A) Comprising an amino acid sequence which is at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to SEQ ID NO. 17, or (B) Comprising or consisting of the amino acid sequence of SEQ ID NO. 17.
  20. 20. The combination of any one of claims 1-3, wherein the ActRIIB ECD variant comprises the amino acid substitution L33M.

Description

Combination therapy of ActRIIB receptor variants and GLP-1 agonists Cross Reference to Related Applications The present application is an international PCT application claiming priority from U.S. provisional application No. 63/581,428 filed on 8 th month 9 of 2023, U.S. provisional application No. 63/647,506 filed on 14 th 5 th year 2024, and U.S. provisional application No. 63/678,479 filed on 1 th 8 th year 2024, each of which are incorporated herein by reference in their entirety. Reference to electronic sequence Listing The contents of the electronic sequence listing (35PH_005_03WO_SeqList_ST26. Xml; size: 451,034 bytes; and date of creation: 2024, 9, 4) are incorporated herein by reference in their entirety. Technical Field The present disclosure relates to a combination of a tgfβ superfamily ligand binding agent and a GLP-1 agonist and uses thereof for treating metabolic disorders. Background Since the regulation of metabolism and fat storage involves complex biofeedback systems, the treatment of metabolic disorders such as obesity remains elusive. To date, drugs that are effective in regulating metabolic dysfunction often exhibit several side effects that limit their utility in patient populations, particularly in obese patient populations that may require long-term treatment. Thus, additional compositions and methods are needed to treat metabolic disorders including obesity. Disclosure of Invention In some embodiments, the disclosure provides a combination comprising a TGF-beta superfamily ligand binding agent, the binding agent comprising (a) a first polypeptide and a second polypeptide, wherein the first polypeptide and the second polypeptide each comprise (i) a polypeptide comprising an amino acid sequence that is at least 90% identical to an ActRIIB type receptor (ActRIIB) extracellular domain (ECD) variant comprising an amino acid substitution at a position corresponding to position 33 of SEQ ID NO: 2, (ii) an Fc domain monomer, and (iii) a peptide linker connecting the polypeptides to the Fc domain monomer, and (b) a glucagon-like peptide 1 (GLP-1) agonist. The combination of claim 1, wherein the ActRIIB ECD variant exhibits reduced inhibition of BMP-9 and/or BMP-10 compared to a wild type ActRIIB extracellular domain. In some embodiments, the amino acid substitution is selected from L33F, L33Q, L33Y, L33W, L33H, L33R, L33E, L K and L33M. In some embodiments, actRIIB ECD variants include the amino acid substitution L33F. In some embodiments, actRIIB ECD variants comprise or consist of an amino acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID No. 10. In some embodiments, actRIIB ECD variants include the amino acid substitution L33Q. In some embodiments, actRIIB ECD variants comprise or consist of an amino acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID No. 11. In some embodiments, actRIIB ECD variants include the amino acid substitution L33Y. In some embodiments, actRIIB ECD variants comprise or consist of an amino acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID No. 12. In some embodiments, actRIIB ECD variants include the amino acid substitution L33W. In some embodiments, actRIIB ECD variants comprise or consist of an amino acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID No. 13. In some embodiments, actRIIB ECD variants include the amino acid substitution L33H. In some embodiments, actRIIB ECD variants comprise or consist of an amino acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID No. 14. In some embodiments, actRIIB ECD variants include the amino acid substitution L33R. In some embodiments, actRIIB ECD variants comprise or consist of an amino acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID No. 15. In some embodiments, actRIIB ECD variants include the amino acid substitution L33E. In some embodiments, actRIIB ECD variants comprise or consist of an amino acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID No. 16. In some embodiments, actRIIB ECD variants include the amino acid substitution L33K. In some embodiments, actRIIB ECD variants comprise or consist of an amino acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID No. 17. In some embodiments, actRIIB ECD variants include the amino acid substitution L33M. In some embodiments, actRIIB ECD variants comprise or consist of an amino acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or