One-armed antigen-binding molecule and its use

Abstract

Provides a one-armed antigen-binding molecule. [Solution] An antigen-binding molecule is provided, comprising an antigen-binding moiety that specifically binds to an antigen and an Fc polypeptide containing first and second Fc region variants, wherein the first Fc region variant is fused to the antigen-binding moiety, but the second Fc region variant is not fused to the antigen-binding moiety or any other antigen-binding moiety that binds to the antigen, and which has substantially reduced Fcγ receptor binding activity and maintained or increased C1q binding activity compared to an antigen-binding molecule containing a parent Fc region. An antigen-binding molecule of this format can enhance the clearance of the target virus while reducing the risk of ADE.

Claims

1. (i) A first antigen-binding moiety that specifically binds to the antigen, (ii) Fc polypeptide and An antigen-binding molecule containing, Fc polypeptide, A first Fc region variant and a second Fc region variant, each containing at least one amino acid modification relative to the parent Fc region. The variant includes a first Fc region variant fused to a first antigen-binding region, wherein the second Fc region variant is not fused to any other antigen-binding region that specifically binds to the antigen. An antigen-binding molecule having substantially reduced FcγR binding activity and maintained or increased C1q binding activity compared to an antigen-binding molecule containing a parent Fc region.

2. The antigen-binding molecule according to claim 1, further comprising a second antigen-binding moiety that specifically binds to an epitope on an antigen different from the epitope on the antigen bound by the first antigen-binding moiety.

3. The antigen-binding molecule according to claim 1, further comprising a second antigen-binding moiety that specifically binds to the same epitope on the antigen as the epitope bound by the first antigen-binding moiety.

4. The antigen-binding molecule according to claim 2 or 3, wherein a second antigen-binding portion is fused to the N-terminus of a first antigen-binding portion.

5. The antigen-binding molecule according to any one of claims 1 to 4, wherein the first antigen-binding portion and / or the second antigen-binding portion comprises Fab, scFv, VHH, VL, VH, a single-domain antibody, or a ligand.

6. An antigen-binding molecule according to any one of claims 1 to 5, wherein each of the first Fc region variant and the second Fc region variant contains Ala at position 234 and Ala at position 235 according to EU numbering.

7. Each of the first Fc region variant and the second Fc region variant corresponds to one of the following (a) to (c) in EU numbering: (a) 267th, 268th, and 324th; (b) 236th, 267th, 268th, 324th, and 332nd; and (c) 326th and 333rd The antigen-binding molecule according to claim 6, comprising further amino acid modifications at the position.

8. The first Fc region variant and the second Fc region variant are, according to EU numbering, as follows: (a) Glu at rank 267; (b) Phe at 268th place; (c) Thr at 324th place; (d) Ala in 236th place; (e) Glu at rank 332; (f) Ala, Asp, Glu, Met, or Trp at position 326; and (g) Ser at 333rd place The antigen-binding molecule according to claim 7, comprising an amino acid selected from the group consisting of the following.

9. The first Fc region variant and the second Fc region variant are, according to EU numbering, as follows: (a) Ala at rank 434; (b) Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440; (c) Leu at position 428, Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440; (d) Leu at 428th place, and Ala at 434th place; and (e) Leu at 428th, Ala at 434th, Arg at 438th, and Glu at 440th An antigen-binding molecule according to any one of claims 1 to 8, comprising an amino acid selected from the group consisting of the following.

10. The antigen-binding molecule according to any one of claims 1 to 9, wherein each of the first Fc region variant and the second Fc region variant comprises at least one amino acid modification that enhances hexamer formation.

11. The antigen-binding molecule according to any one of claims 1 to 10, wherein each of the first Fc region variant and the second Fc region variant comprises at least one amino acid modification that facilitates association between the first Fc region variant and the second Fc region variant.

12. The antigen-binding molecule according to any one of claims 1 to 11, wherein the risk of antibody-dependent enhancement (ADE) of intracellular entry of a pathogen expressing the aforementioned antigen is reduced.

13. An antigen-binding molecule according to any one of claims 1 to 12, which mobilizes C1q to eliminate a pathogen or cells infected with the pathogen via complement-dependent cell-mediated cytotoxicity (CDC).

14. A pharmaceutical composition comprising an antigen-binding molecule according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier.

15. An isolated nucleic acid encoding an antigen-binding molecule according to any one of claims 1 to 13.

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