KR-20260064751-A - Molecules for regulating immune responses

Abstract

The present disclosure provides a molecule comprising a binding domain that specifically binds to a target antibody 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 a pathogenic antibody.

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 a binding domain that specifically binds to a target antibody; and It comprises a second polypeptide containing a second Fc domain; The first Fc domain and the second Fc domain form a homodimer or heterodimer of the first polypeptide and the second polypeptide, and the first and/or second Fc domain comprises one or more mutated amino acid residues and has an increased binding affinity for FcγRIIB compared to the corresponding wild-type Fc domain; A molecule in which, when two molecules bind to the target antibody, an immune complex having enhanced binding kinetics with FcγRIIB is formed compared to an immune complex comprising a target antibody bound to two corresponding molecules having a wild-type Fc domain.
2. In claim 1, the second polypeptide further comprises a binding domain that specifically binds to a target antibody, and the molecule is a homodimer.
3. In claim 1, the second polypeptide further comprises a binding domain that specifically binds to a target antibody, and the molecule is a heterodimer.
4. In claim 1, the second polypeptide does not include a binding domain that specifically binds to a target antibody, and the molecule is a heterodimer.
5. A molecule according to claim 1, wherein when two molecules bind to the target antibody, an immune complex having enhanced binding kinetics with FcγRIIB is formed compared to an immune complex comprising the target antibody bound to only a single molecule.
6. A molecule according to any one of claims 1 to 5, wherein the enhanced bonding kinetics comprises an increase in bonding rate, a decrease in dissociation rate, and/or a change in the equilibrium dissociation constant.
7. A molecule according to any one of claims 1 to 6, wherein the enhanced binding kinetics results in an increase in the binding strength, stability, strength, frequency, and/or duration of the binding between the immune complex and FcγRIIB.
8. In any one of claims 1 to 7, the target antibody is a molecule that is a pathogenic antibody.
9. In any one of claims 1 to 8, the target antibody is a molecule that is an autoantibody.
10. In any one of claims 1 to 9, the target antibody is a molecule that is a secreted antibody.
11. In any one of claims 1 to 8, the target antibody is a molecule that is a membrane-bound antibody or an autoreactive B cell receptor.
12. A molecule according to any one of claims 1 to 11, wherein the first and/or second Fc domain comprising one or more mutated amino acid residues does not have increased binding affinity for FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB, and/or FcRn compared to the corresponding wild-type Fc domain.
13. A molecule according to any one of claims 1 to 12, wherein the first and/or second Fc domain comprising one or more mutated amino acid residues has a reduced binding affinity for FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB, and/or FcRn compared to the corresponding wild-type Fc domain.
14. A molecule according to any one of claims 1 to 13, wherein the first and/or second Fc domain comprising one or more mutated amino acid residues substantially does not have binding affinity for FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB, and/or FcRn compared to the corresponding wild-type Fc domain.
15. A molecule according to any one of claims 1 to 14, wherein the enhanced binding kinetics comprises at least 10% greater binding affinity of the immune complex for FcγRIIB.
16. In claim 15, the above-mentioned binding affinity greater than 10% comprises a binding affinity of at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% or more.
17. In claim 15, the molecule is a molecule that binds to FcγRIIB with an affinity in the range of about 1 μM to 0.001 μM.
18. In claim 15, the molecule is a molecule that binds to FcγRIIB with an affinity in the range of about 1 μM to 0.001 μM.
19. In claim 15, the molecule is a molecule that binds to FcγRIIB with an affinity within the range of about 0.1 μM to 0.01 μM.
20. In claim 15 or 16, the binding affinity comprises the binding affinity for a cell line overexpressing FcγRIIB ( e.g. , CHO cell line) as measured by flow cytometry.

Description

Molecules for regulating immune responses Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63/517,101 filed August 1, 2023 and U.S. Provisional Application No. 63/517,104 filed August 1, 2023. The full text of the aforementioned applications is incorporated herein by reference. Unregulated immune responses to pathogens or autoantigens are implicated in many diseases, such as autoimmune diseases, chronic inflammatory diseases, and allergies. Autoimmune diseases occur when the body's immune system attacks its own healthy cells. There are various types of autoimmune diseases, such as Graves' disease, Type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, preeclampsia, multiple sclerosis, and vasculitis. Autoantibodies target autoantigens and are produced by pathogenic plasma cells. Autoantibodies are considered markers of diseases associated with unregulated immune responses ( e.g. , autoimmune diseases), and methods to target and deplete these antibodies in patients have been studied. However, therapeutic approaches for autoimmune diseases and other conditions associated with uncontrolled immune responses often lead to the depletion of antibodies that provide an appropriate immune response against invading pathogens, rather than selectively depleting pathogenic autoantibodies. The present disclosure provides a molecule for selectively depleting and/or neutralizing a target antibody. In some embodiments, the molecule described herein comprises a first polypeptide comprising a first Fc domain and a binding domain that specifically binds to a target antibody, and a second polypeptide comprising a second Fc domain. In some embodiments, the first Fc domain and the second Fc domain form a homodimer or a heterodimer of the first polypeptide and the second polypeptide. In some embodiments, the second polypeptide further comprises a binding domain that specifically binds to a target antibody, and the molecule is a homodimer. In some embodiments, the second polypeptide further comprises a binding domain that specifically binds to a target antibody, and the molecule is a heterodimer. In some embodiments, the second polypeptide does not comprise a binding domain that specifically binds to a target antibody, and the molecule is a heterodimer. In some embodiments, the first and/or second Fc domain comprises one or more mutated amino acid residues and has an increased binding affinity for an internalization receptor ( e.g. , FcγRIIB) compared to the corresponding wild-type Fc domain. In some embodiments, when one or two molecules bind to a target antibody, an immune complex is formed. In some embodiments, an immune complex formed by the one molecule and the target antibody described herein has enhanced binding kinetics with FcγRIIB compared to an immune complex comprising a target antibody bound to one corresponding molecule having a wild-type Fc domain. In some embodiments, an immune complex formed by the two molecules and the target antibody described herein has enhanced binding kinetics with FcγRIIB compared to an immune complex comprising a target antibody bound to two corresponding molecules having a wild-type Fc domain. This enhanced binding kinetics increases the clearance of the immune complex. In one embodiment, the present disclosure provides a molecule comprising: a first polypeptide comprising a first Fc domain and a binding domain that specifically binds to a target antibody; 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, wherein the first and/or second Fc domain comprises one or more mutated amino acid residues and has an increased binding affinity for FcγRIIB compared to the corresponding wild-type Fc domain; wherein when the two molecules bind to a target antibody, an immune complex is formed having enhanced binding kinetics with FcγRIIB compared to an immune complex comprising a target antibody bound to two corresponding molecules having wild-type Fc domains. In some embodiments, the second polypeptide further comprises a binding domain that specifically binds to a target antibody, and the molecule is a homodimer. In some embodiments, the second polypeptide further comprises a binding domain that specifically binds to a target antibody, and the molecule is a heterodimer. In some embodiments, the second polypeptide does not comprise a binding domain that specifically binds to a target antibody, and the molecule is a heterodimer. In some embodiments, when two molecules bind to a target antibody, an immune complex is formed that has enhanced binding kinetics with FcγRIIB compared to an immune complex containing a target antibody bound to only a single molecule. In some embodiments, enhanced binding kinetics include an increase in binding rate, a decrease in dissocia