KR-20260064754-A - Molecules for regulating autoimmune responses

Abstract

The present disclosure provides , in particular, a molecule comprising an autoantibody-binding domain and at least one modified Fc domain. The present disclosure also provides a method and a composition that allow for the selective depletion and/or neutralization of pathogenic autoantibodies.

Inventors

• 구티에레스, 다리오 에이.
• 로흐텐베르흐, 마이커 이. 더블유.
• 카필리, 앨런 디.

Assignees

• 메리다 바이오사이언시스, 인크.

Dates

Publication Date

20260507

Application Date

20240801

Priority Date

20230801

Claims (20)

1. As a molecule, A first polypeptide comprising a first Fc domain and an autoantibody-binding domain that binds to an anti-PLA2R autoantibody; and Comprising a second polypeptide comprising a second Fc domain; A molecule in which the first Fc domain and the second Fc domain form a homomer or heteromer of the first polypeptide and the second polypeptide.
2. In claim 1, the second polypeptide further comprises an autoantibody-binding domain that binds to an anti-PLA2R autoantibody, and the molecule is a homomer.
3. In claim 1, the second polypeptide further comprises an autoantibody-binding domain that binds to an anti-PLA2R autoantibody, and the molecule is a heterodimer.
4. In claim 1, the second polypeptide does not include an autoantibody-binding domain that binds to an anti-PLA2R autoantibody, and the molecule is a heterodimer.
5. In claim 1, the molecule wherein the autoantibody-binding domain is covalently connected to the first Fc domain.
6. In claim 5, the molecule wherein the C-terminus of the autoantibody-binding domain is covalently connected to the N-terminus of the first Fc domain.
7. In claim 5, the molecule wherein the N-terminus of the autoantibody-binding domain is covalently connected to the C-terminus of the first Fc domain.
8. A molecule according to any one of claims 1 to 7, wherein the first and second Fc domains form a heterodimer due to a knop-in-hole (KIH) mutation.
9. In paragraph 8, the above KIH mutation is a molecule comprising Y349T and T394F according to the EU numbering system.
10. In claim 9, the molecule wherein the first Fc domain comprises the Y349T mutation and the second Fc domain comprises the T394F mutation.
11. In paragraph 8, the KIH mutation comprises T366W, S354C, T366S, L368A, Y407V, and Y349C according to the EU numbering system.
12. In claim 11, according to the EU numbering scheme, the molecule, wherein the first Fc domain comprises T366W and S354C mutations and the second Fc domain comprises T366S, L368A, Y407V, and Y349C mutations.
13. A molecule according to any one of claims 1 to 12, wherein the first and/or second Fc domain comprises an IgG1 isotype.
14. In paragraph 13, the molecule wherein the first and/or second Fc domain comprises a human IgG1 isotype.
15. A molecule according to any one of claims 1 to 14, wherein the first and/or second Fc domain comprises one or more mutated amino acid residues that increase the half-life.
16. In paragraph 15, the molecule wherein the first and/or second Fc domain comprises one of the mutated amino acid residues of M252Y, S254T, and T256E according to the EU numbering scheme.
17. A molecule according to claim 15 or 16, wherein the first and/or second Fc domain comprises a combination of mutated amino acid residues of M252Y, S254T, and T256E according to the EU numbering scheme.
18. In paragraph 15, the molecule wherein the first and/or second Fc domain comprises one or more of the mutated amino acid residues of M428L and N434S according to the EU numbering scheme.
19. A molecule according to claim 15 or 18, wherein the first and/or second Fc domain comprises a combination of mutated amino acid residues of M428L and N434S according to the EU numbering scheme.
20. A molecule according to any one of claims 1 to 19, wherein the first and/or second Fc domain comprises one or more mutated amino acid residues that alter its binding to an internalization receptor on a cell, and said internalization receptor capable of inducing degradation by shuttleing its cargo to the lysosome of said cell.

Description

Molecules for regulating autoimmune responses Cross-reference of related applications This application claims the benefit of U.S. Provisional Application No. 63/517,104 filed on August 1, 2023. The contents of the aforementioned application are incorporated herein by reference in their entirety. Autoimmune diseases occur when the body's immune system attacks its own healthy cells. There are various types of autoimmune diseases, such as primary membranous nephropathy, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, preeclampsia, multiple sclerosis, and vasculitis. Autoantibodies are antibodies that target autoantigens and healthy cells, and they are produced by pathogenic plasma cells. Autoantibodies are considered markers of immune diseases, and methods to target and deplete autoantibodies in patients with autoimmune diseases have been studied. However, therapeutic approaches to autoimmune diseases often lead to the depletion of antibodies that provide an appropriate immune response against invading pathogens, rather than selectively depleting pathogenic autoantibodies. Above all, in some embodiments, the present disclosure provides a molecule that selectively targets and neutralizes and/or depletes pathogenic autoantibodies in a subject. The molecule described herein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises an autoantibody-binding domain and a first Fc domain, and the second polypeptide comprises a second Fc domain. As described herein, such a molecule neutralizes and depletes specific pathogenic autoantibodies. In some embodiments, the targeting and depletion of autoantibodies are achieved through a mechanism that targets immune complexes containing autoantibodies to the lysosomes of cells for degradation. The molecule described herein may be used for the treatment of autoimmune diseases such as membranous nephropathy and/or other autoimmune diseases implicated by autoantibodies targeting the M-type phospholipase A2 receptor (PLA2R). In some embodiments, the molecule comprises a PLA2R autoantigen domain, or an autoantigen domain that is a fragment or variant thereof. In addition to comprising an autoantibody-binding domain that targets autoantibodies, the molecule described herein may also comprise a modification that targets specific internalization receptors. In some embodiments, the molecule described herein comprises an Fc domain that binds to a receptor on a cell that induces the internalization of the bound molecule. Such molecules allow for the binding of an anti-PLA2R autoantibody via the autoantigen domain, and targeting of lysosomes for degradation via the binding of the internalization receptor. In some embodiments, the molecule may comprise a modification in its first and/or second Fc domain that increases its binding affinity to Fc-gamma-IIB (FcγRIIB). In some embodiments, the first and/or second Fc domain of the molecule may comprise a modification that increases its binding affinity to the human newborn Fc receptor (FcRn). In some embodiments, the molecules described herein comprise an antigen-binding domain, wherein the antigen-binding domain binds to a receptor on a cell that internalizes the bound molecule ( e.g. , see FIG. 3 ). In some embodiments, the antigen-binding domain binds to an internalization receptor such as FcγRIIB, ASPGR, and/or FcRn. Molecules targeting an internalization receptor such as FcγRIIB can suppress/deplete autoantigen-specific B cells in which autoantibodies are expressed on the cell surface ( e.g. , as described in Chu et al., Mol Immunol 45:3926-3933 (2008), the full text of which is incorporated herein by reference). All of these strategies aim to deplete specific autoantibodies involved in autoimmune diseases. In some embodiments, the autoantibody is an anti-PLA2R autoantibody, and the disease is membranous nephropathy or another autoimmune disease caused by the anti-PLA2R autoantibody. The molecule may include a PLA2R autoantigen domain and an Fc domain targeting the anti-PLA2R autoantibody and/or an antigen-binding domain targeting the complex (molecule and autoantibody) to the cell's lysosome for selective degradation. In one embodiment, the present disclosure provides a molecule comprising: a first polypeptide comprising a first Fc domain and an autoantibody-binding domain that binds to an anti-PLA2R autoantibody; and a second polypeptide comprising a second Fc domain, wherein the first Fc domain and the second Fc domain form a homodimer or heterodimer of the first polypeptide and the second polypeptide. In some embodiments, the second polypeptide further comprises an autoantibody-binding domain that binds to an anti-PLA2R autoantibody, and the molecule is a homomer. In some embodiments, the second polypeptide further comprises an autoantibody-binding domain that binds to an anti-PLA2R autoantibody, and the molecule is a heterodimer. In some embodiment