Anti-hepatitis B virus antibody and uses thereof

Patent metadata

Field	Value
Publication number	US-12410239-B2
Application number	US-202017613322-A
Country	US
Kind code	B2
Filing date	May 22, 2020
Priority date	May 23, 2019
Publication date	Sep 9, 2025
Grant date	Sep 9, 2025

Abstract

Disclosed are antibodies to anti-hepatitis B surface antigen (HBsAg) (especially humanized antibodies), nucleic acid molecules encoding same, methods for preparing same, and pharmaceutical compositions containing same. The antibodies have higher affinity for HBsAg at neutral pH than at acidic pH, thereby significantly enhancing the virus clearance efficiency and prolonging the virus inhibition time. The antibodies and the pharmaceutical compositions can be used for preventing and/or treating HBV infections or diseases related to HBV infections (e.g., hepatitis B), for neutralizing the virulence of HBV in a subject (e.g., a human), for reducing the serum level of HBV DNA and/or HBsAg in the body of the subject, or for activating the humoral immune response of the subject (e.g., a chronic HBV infected or chronic hepatitis B patient) against HBV.

First claim

What is claimed is:

1. An antibody or antigen-binding fragment thereof capable of specifically binding to HBsAg, wherein the antibody or antigen-binding fragment thereof binds to HBsAg with higher affinity at neutral pH than at acidic pH, and the antibody or antigen-binding fragment thereof comprises:
(1) a VH comprising three CDRs:
HCDR1 consisting of the amino acid sequence of SEQ ID NO:8,
HCDR2 consisting of the amino acid sequence of SEQ ID NO: 9, and
HCDR3 consisting of the amino acid sequence of SEQ ID NO: 10;
and
a VL comprising three CDRs:
LCDR1 consisting of the amino acid sequence of SEQ ID NO: 11,
LCDR2 consisting of the amino acid sequence of SEQ ID NO: 12, and
LCDR3 consisting of the amino acid sequence of SEQ ID NO: 13;
(2) a VH comprising three CDRs:
HCDR1 consisting of the amino acid sequence of SEQ ID NO: 14,
HCDR2 consisting of the amino acid sequence of SEQ ID NO: 15, and
HCDR3 consisting of the amino acid sequence of SEQ ID NO: 16;
and
a VL comprising three CDRs:
LCDR1 consisting of the amino acid sequence of SEQ ID NO: 11,
LCDR2 consisting of the amino acid sequence of SEQ ID NO: 12, and
LCDR3 consisting of the amino acid sequence of SEQ ID NO: 13;
(3) a VH comprising three CDRs:
HCDR1 consisting of the amino acid sequence of SEQ ID NO: 20,
HCDR2 consisting of the amino acid sequence of SEQ ID NO: 21, and
HCDR3 consisting of the amino acid sequence of SEQ ID NO: 22;
and
a VL comprising three CDRs:
LCDR1 consisting of the amino acid sequence of SEQ ID NO: 23,
LCDR2 consisting of the amino acid sequence of SEQ ID NO: 12, and
LCDR3 consisting of the amino acid sequence of SEQ ID NO: 13;
or
(4) a VH comprising three 3 CDRs:
HCDR1 consisting of the amino acid sequence of SEQ ID NO: 17,
HCDR2 consisting of the amino acid sequence of SEQ ID NO: 18, and
HCDR3 consisting of the amino acid sequence of SEQ ID NO: 10;
and
a VL comprising three CDRs:
LCDR1 consisting of the amino acid sequence of SEQ ID NO: 19,
LCDR2 consisting of the amino acid sequence of SEQ ID NO: 12, and
LCDR3 consisting of the amino acid sequence of SEQ ID NO: 13.

2. The antibody or antigen-binding fragment thereof according to claim 1 , wherein the antibody or antigen-binding fragment thereof further comprises a framework region of a human immunoglobulin, and the framework region optionally comprises at least one back mutation from human residues to murine residues.

3. The antibody or antigen-binding fragment thereof according to claim 1 , wherein the antibody or antigen-binding fragment thereof comprises:
(1) a VH consisting of the amino acid sequence of SEQ ID NO: 1 and a VL consisting of the amino acid sequence of SEQ ID NO: 2;
(2) a VH consisting of the amino acid sequence of SEQ ID NO: 3 and a VL consisting of the amino acid sequence of SEQ ID NO: 2;
(3) a VH consisting of the amino acid sequence of SEQ ID NO: 4 and a VL consisting of the amino acid sequence of SEQ ID NO: 5; or
(4) a VH consisting of the amino acid sequence of SEQ ID NO: 6 and a VL consisting of the amino acid sequence of SEQ ID NO: 7.

4. The antibody or antigen-binding fragment thereof according to claim 1 , wherein the antibody or antigen-binding fragment thereof further comprises a constant region derived from a human immunoglobulin.

5. The antibody or antigen-binding fragment thereof according to claim 4 , wherein the antibody or antigen-binding fragment thereof comprises a variant of a human IgGI heavy chain constant region, the variant has the following substitution as compared to a wild-type sequence from which it is derived: (i) M252Y, N286E, N434Y; or, (ii) K326D, L328Y; wherein the amino acid positions are positions according to the Kabat numbering system.

6. The antibody or antigen-binding fragment thereof according to claim 1 , wherein the antibody or antigen-binding fragment thereof comprises:
(1) a heavy chain comprising a VH consisting of the amino acid sequence of SEQ ID NO: 1 and a CH consisting of the amino acid sequence of SEQ ID NO: 57, and a light chain comprising a VL consisting of the amino acid sequence of SEQ ID NO: 2 and a CL consisting of the amino acid sequence of SEQ ID NO: 58;
(2) a heavy chain comprising a VH consisting of the amino acid sequence of SEQ ID NO: 1 and a CH consisting of the amino acid sequence of SEQ ID NO: 47, and a light chain comprising a VL consisting of the amino acid sequence of SEQ ID NO: 2 and a CL consisting of the amino acid sequence of SEQ ID NO: 58;
(3) a heavy chain comprising a VH consisting of the amino acid sequence of SEQ ID NO: 1 and a CH consisting of the amino acid sequence of SEQ ID NO: 48, and a light chain comprising a VL consisting of the amino acid sequence of SEQ ID NO: 2 and a CL consisting of the amino acid sequence of SEQ ID NO: 58;
(4) a heavy chain comprising a VH consisting of the amino acid sequence of SEQ ID NO: 3 and a CH consisting of the amino acid sequence of SEQ ID NO: 57, and a light chain comprising a VL consisting of the amino acid sequence of SEQ ID NO: 2 and a CL consisting of the amino acid sequence of SEQ ID NO: 58;
(5) a heavy chain comprising a VH consisting of the amino acid sequence of SEQ ID NO: 3 and a CH consisting of the amino acid sequence of SEQ ID NO: 47, and a light chain comprising a VL consisting of the amino acid sequence of SEQ ID NO: 2 and a CL consisting of the amino acid sequence of SEQ ID NO: 58;
(6) a heavy chain comprising a VH consisting of the amino acid sequence of SEQ ID NO: 3 and a CH consisting of the amino acid sequence of SEQ ID NO: 48, and a light chain comprising a VL consisting of the amino acid sequence of SEQ ID NO: 2 and a CL consisting of the amino acid sequence of SEQ ID NO: 58;
(7) a heavy chain comprising a VH consisting of the amino acid sequence of SEQ ID NO: 4 and a CH consisting of the amino acid sequence of SEQ ID NO: 57, and a light chain comprising a VL consisting of the amino acid sequence of SEQ ID NO: 5 and a CL consisting of the amino acid sequence of SEQ ID NO: 58;
(8) a heavy chain comprising a VH consisting of the amino acid sequence of SEQ ID NO: 4 and a CH consisting of the amino acid sequence of SEQ ID NO: 47, and a light chain comprising a VL consisting of the amino acid sequence of SEQ ID NO: 5 and a CL consisting of the amino acid sequence of SEQ ID NO: 58;
(9) a heavy chain comprising a VH consisting of the amino acid sequence of SEQ ID NO: 4 and a CH consisting of the amino acid sequence of SEQ ID NO: 48, and a light chain comprising a VL consisting of the amino acid sequence of SEQ ID NO: 5 and a CL consisting of the amino acid sequence of SEQ ID NO: 58;
(10) a heavy chain comprising a VH consisting of the amino acid sequence of SEQ ID NO: 6 and a CH consisting of the amino acid sequence of SEQ ID NO: 57, and a light chain comprising a VL consisting of the amino acid sequence of SEQ ID NO: 7 and a CL consisting of the amino acid sequence of SEQ ID NO: 58;
(11) a heavy chain comprising a VH consisting of the amino acid sequence of SEQ ID NO: 6 and a CH consisting of the amino acid sequence of SEQ ID NO: 47, and a light chain comprising a VL consisting of the amino acid sequence of SEQ ID NO: 7 and a CL consisting of the amino acid sequence of SEQ ID NO: 58; or
(12) a heavy chain comprising a VH consisting of the amino acid sequence of SEQ ID NO: 6 and a CH consisting of the amino acid sequence of SEQ ID NO: 48, and a light chain comprising a VL consisting of the amino acid sequence of SEQ ID NO: 7 and a CL consisting of the amino acid sequence of SEQ ID NO: 58.

7. The antibody or antigen-binding fragment thereof according to claim 1 , wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of scFv, Fab, Fab′, (Fab′) 2 , Fv fragment, diabody, bispecific antibody,

Assignees

• Univ Xiamen
• Yang Sheng Tang Co Ltd

Inventors

• Luo Wenxin
• Wen Can
• Xiang Xinchu
• Tang Jixian
• Wu Yangtao
• Zhang Tianying
• Yuan Quan
• Xia Ningshao

Classifications

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• C07K2317/622

  Single chain antibody (scFv) · CPC title

• C07K2317/567

  Framework region [FR] · CPC title

• C07K2317/52

  Constant or Fc region; Isotype · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title