IP Library › Granted Patent US 12,410,239
Granted Patent B2
US 12,410,239 · App. 17/613,322 · Granted Sep 9, 2025

Anti-hepatitis B virus antibody and uses thereof

Inventors: Wenxin Luo (Xiamen, CN); Can Wen (Xiamen, CN); Xinchu Xiang (Xiamen, CN); Jixian Tang (Xiamen, CN); Yangtao Wu (Xiamen, CN); Tianying Zhang (Xiamen, CN); Quan Yuan (Xiamen, CN); Ningshao Xia (Xiamen, CN)
Assignees: XIAMEN UNIVERSITY; YANG SHENG TANG COMPANY, LTD.
C07K16/082A61P31/20A61K2039/505A61K2039/575C07K2317/24C07K2317/515C07K2317/52C07K2317/56C07K2317/565C07K2317/567C07K2317/622C07K2317/76C07K2317/92
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,410,239
App. No.
17/613,322
Granted
Sep 9, 2025
Kind
B2
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.

Claims (90)

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, multispecific antibody, probody, chimeric antibody and humanized antibody.

8. An isolated nucleic acid molecule, which encodes the antibody or antigen-binding fragment thereof according to claim 1 , or its heavy chain variable region and light chain variable region.

9. A vector, which comprises an isolated nucleic acid molecule encoding the antibody or antigen-binding fragment thereof according to claim 1 or its heavy chain variable region and light chain variable region.

10. A host cell, comprising: (i) an isolated nucleic acid molecule encoding the antibody or antigen-binding fragment thereof according to claim 1 or its heavy chain variable region and light chain variable region, or (ii) a vector comprising the isolated nucleic acid molecule.

11. A method for preparing the antibody or antigen-binding fragment thereof according to claim 1 , the method comprising:

culturing a host cell comprising an isolated nucleic acid molecule encoding the antibody or antigen-binding fragment thereof under a condition that allows the expression of the antibody or antigen-binding fragment thereof, and

recovering the antibody or antigen-binding fragment thereof from the cultured host cell culture.

12. A pharmaceutical composition, comprising the antibody or antigen-binding fragment thereof according to claim 1 , and a pharmaceutically acceptable carrier and/or excipient.

13. A method for treatment of an HBV infection or HBV infection-associated disease in a subject, for neutralizing a virulence of HBV in a subject, for reducing a serum level of HBV DNA and/or HBsAg in a subject, and/or for activating a humoral immune response against HBV in a subject, the method comprising:

administering an effective amount of the antibody or antigen-binding fragment thereof according to claim 1 , or a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof, to a subject in need thereof.

14. The antibody or antigen-binding fragment thereof according to claim 2 , wherein:

(i) the antibody or antigen-binding fragment thereof comprises:

a heavy chain framework region contained in an amino acid sequence encoded by IGHV4-4*08, and

a light chain framework region contained in an amino acid sequence encoded by IGKV1-39*01,

wherein the heavy chain framework region and/or the light chain framework region optionally comprises at least one back mutation from human residues to murine residues; or,

(ii) the VH of the antibody or antigen-binding fragment thereof comprises:

a VH FR1 consisting of the amino acid sequence of SEQ ID NO: 24,

a VH FR2 consisting of the amino acid sequence of SEQ ID NO: 25,

a VH FR3 consisting of the amino acid sequence of SEQ ID NO: 26, and

a VH FR4 consisting of the amino acid sequence of SEQ ID NO: 27;

and/or

the VL of the antibody or antigen-binding fragment thereof comprises:

a VL FR1 consisting of the amino acid sequence of SEQ ID NO: 28,

a VL FR2 consisting of the amino acid sequence of SEQ ID NO: 29,

a VL FR3 consisting of the amino acid sequence of SEQ ID NO: 30, and

a VL FR4 consisting of the amino acid sequence of SEQ ID NO: 31.

15. The antibody or antigen-binding fragment thereof according to claim 4 , wherein:

(i) the antibody or antigen-binding fragment thereof comprises a heavy chain constant region (CH) consisting of the amino acid sequence of SEQ ID NO: 47 or 48 or 57; and/or,

(ii) the antibody or antigen-binding fragment thereof comprises a light chain constant region (CL) consisting of the amino acid sequence of SEQ ID NO: 58.

16. The method according to claim 13 , wherein the subject is a human.

17. The method according to claim 13 , wherein the subject is a person having chronic HBV infection or chronic hepatitis B.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 6, 2022
From: LUO, WENXIN; WEN, CAN; XIANG, XINCHU; TANG, JIXIAN; WU, YANGTAO; ZHANG, TIANYING; YUAN, QUAN; XIA, NINGSHAO
To: XIAMEN UNIVERSITY; YANG SHENG TANG COMPANY, LTD.
Reel/Frame 059408/0687 →
Priority Claims (1)
CN 201910432602.7 · May 23, 2019 · national
Continuity (1)
Related Publication 20220235117A1 · Jul 28, 2022
References Cited (53)
US 9751914B2 · Yuan et al. · 2017 [cited by applicant]
US 10246494B2 · Yuan et al. · 2019 [cited by applicant]
US 10548973B2 · Zhang et al. · 2020 [cited by applicant]
US 10556949B2 · Igawa et al. · 2020 [cited by applicant]
US 20110111406A1 · Igawa et al. · 2011 [cited by applicant]
US 20120264921A1 · Kim et al. · 2012 [cited by applicant]
US 20140255398A1 · Igawa et al. · 2014 [cited by applicant]
US 20150050269A1 · Igawa et al. · 2015 [cited by applicant]
US 20150246948A1 · Yuan et al. · 2015 [cited by applicant]
US 20170022270A1 · Igawa et al. · 2017 [cited by applicant]
US 20170326231A1 · Yoon et al. · 2017 [cited by applicant]
US 20180002382A1 · Yuan et al. · 2018 [cited by applicant]
US 20180037634A1 · Viswanathan et al. · 2018 [cited by applicant]
US 20190185557A1 · Igawa et al. · 2019 [cited by applicant]
US 20190247494A1 · Zhang et al. · 2019 [cited by applicant]
US 20190389939A1 · Luo et al. · 2019 [cited by applicant]
US 20200115447A1 · Igawa et al. · 2020 [cited by applicant]
US 20200147205A1 · Zhang et al. · 2020 [cited by applicant]
CN 102906111A · 2013 [cited by applicant]
CN 103483421A · 2014 [cited by applicant]
CN 104093424A · 2014 [cited by applicant]
CN 106046155A · 2016 [cited by applicant]
CN 106480070A · 2017 [cited by applicant]
CN 106565840A · 2017 [cited by applicant]
CN 108456686A · 2018 [cited by applicant]
CN 108690134A · 2018 [cited by applicant]
CN 109414496A · 2019 [cited by applicant]
EP 2762493A1 · 2014 [cited by applicant]
JP 2000253878A · 2000 [cited by applicant]
JP 2012521772A · 2012 [cited by applicant]
JP 2017536832A · 2017 [cited by applicant]
KR 1020180084045A · 2018 [cited by applicant]
RU 2616236C1 · 2017 [cited by applicant]
WO WO2009125825A1 · 2009 [cited by applicant]
WO WO2010112316A1 · 2010 [cited by applicant]
WO WO2013047729A1 · 2013 [cited by applicant]
WO WO2013047748A1 · 2013 [cited by applicant]
WO WO2017176319A1 · 2017 [cited by applicant]
WO WO2018052556A1 · 2018 [cited by applicant]
WO WO2018184593A1 · 2018 [cited by applicant]
WO WO2018195165A1 · 2018 [cited by applicant]
WO WO2018206748A1 · 2018 [cited by applicant]
Rudikoff S, Giusti AM, Cook WD, Scharff MD. Single amino acid substitution altering antigen-binding specificity. Proc Natl Acad Sci USA. Mar. 1982;79(6):1979-83. (Year: 1982). [cited by examiner]
International Search Report issued on Aug. 24, 2020 in PCT/CN2020/091739 filed on May 22, 2020, citing documents AA-AC, AO-AR, AX and AY therein, 5 pages. [cited by applicant]
Wen, C. et al., “Advance in research on recycling antibody,” Chin. J. Biotech., vol. 35, No. 2, 2019, pp. 183-194 (with English abstract). [cited by applicant]
Yang, D. et al., “Maximizing in vivo target clearance by design of pH-dependent target binding antibodies with altered affinity to FcRn,” MABS, vol. 9, No. 7, 2017, pp. 1105-1117. [cited by applicant]
Bonvin et al., “De novo isolation of antibodies with pH-dependent binding properties”, mAbs, vol. 7, Issue 2, Mar./Apr. 2015, pp. 294-302. [cited by applicant]
Japanese Office Action issued Jun. 4, 2024 in Japanese Patent Application No. 2021-569886 (with English Translation), citing reference 15 therein, 12 pages. [cited by applicant]
Korean Office Action issued May 20, 2024 in Korean Patent Application No. 10-2021-7041773 (with English Translation), citing reference 16 therein, 25 pages. [cited by applicant]
International Search Report issued on Aug. 26, 2020 in PCT/CN2020/091890 filed May 22, 2020 citing documents AA-AK, AO-AS and AX-AZ therein, 22 total pages (with English translation). [cited by applicant]
Xu, L., et al., “Humanization of Therapeutic Antibody of One Hepatitis B Virus and Identification of Its Biological Activity”, Journal of Xiamen University (Natural Science), vol. 56, No. 1, 2017, pp. 72-78 (with Englis… [cited by applicant]
Chaouch, H., et al., “Naturally Occurring Surface Antigen Variants of Hepatitis B Virus in Tunisian Patients” Intervirology, vol. 59, 2016, pp. 36-47. [cited by applicant]
Kang, X., et al., “Single-domain antibody—advances in research and application”, Chinese Journal of Biotechnology, vol. 34, No. 12, 2018, pp. 1974-1984 (with English abstract). [cited by applicant]