BR-112018007121-B1 - ANTIBODY OR A FRAGMENT THEREOF, ANTIGEN-BINDING AND PHARMACEUTICAL COMPOSITION

BR112018007121B1BR 112018007121 B1BR112018007121 B1BR 112018007121B1BR-112018007121-B1

Abstract

ANTIBODY OR ANTIGEN BINDING FRAGMENT THEREOF, HUMANIZED ANTIBODY OR AN ANTIGEN BINDING FRAGMENT THEREOF, ISOLATED NUCLEIC ACID MOLECULE, VECTOR, HOST CELL, METHOD FOR PREPARING THE ANTIBODY OR AN ANTIGEN BINDING FRAGMENT THEREOF, PHARMACEUTICAL COMPOSITION, USE OF THE ANTIBODY OR AN ANTIGEN BINDING FRAGMENT THEREOF, AND METHOD FOR PREVENTING OR TREATING HBV INFECTION OR A DISEASE ASSOCIATED WITH HBV INFECTION. The invention provides an antibody, in particular, a humanized antibody, against the hepatitis B surface antigen (HBsAg), a nucleic acid molecule encoding the same, a method for preparing the same, and a pharmaceutical composition comprising said antibody. The invention also provides the use of the antibody and the pharmaceutical composition. The antibody and the pharmaceutical composition according to the invention can be used to prevent and/or treat HBV infection or a disease associated with HBV infection (such as Hepatitis B), by neutralizing HBV virulence in an individual, such as a human, or by reducing the serum level of HBV DNA and/or HBsAg in an individual.

Inventors

Wenxin Luo
Bing Zhou
Juan Zhang
Quan Yuan
Tianying Zhang
Jun Zhang
Ningshao Xia

Assignees

XIAMEN UNIVERSITY
YANG SHENG TANG COMPANY, LTD

Dates

Publication Date: 20260317
Application Date: 20161009
Priority Date: 20151009

Claims (8)

1. Antibody or antigen-binding fragment thereof that can specifically bind to HBsAg, characterized in that it comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein: the antibody or antigen-binding fragment thereof (4) the VH is as represented in SEQ ID No: 72 and the VL is as represented in SEQ ID No: 201; (5) the VH is as represented in SEQ ID No: 69 and the VL is as represented in SEQ ID No: 189; (10) the VH is as represented in SEQ ID No: 73 and the VL is as represented in SEQ ID No: 202; (16) the VH is as represented in SEQ ID No: 91 and the VL is as represented in SEQ ID No: 205; (17) the VH is as represented in SEQ ID No: 73 and the VL (18) VH is as represented in SEQ ID No: 205; (19) VH is as represented in SEQ ID No: 36 and VL is as represented in SEQ ID No: 187; (27) VH is as represented in SEQ ID No: 20 and VL is as represented in SEQ ID No: 187; or (49) VH is as represented in SEQ ID No: 41 and VL is as represented in SEQ ID No: 187.
2. Antibody, according to claim 1, characterized in that the antigen-binding antibody or fragment thereof is selected from the group consisting of scFv, Fab, Fab’, (Fab’)2, Fv fragment, diabody, bispecific antibody, and polyspecific antibody.
3. Antibody, according to claim 1, characterized in that the antibody or an antigen-binding fragment thereof is an antibody of the IgG isotype or an antigen-binding fragment thereof.
4. Antibody, according to claim 1, characterized in that the antibody or a fragment thereof binding to the antigen is labeled.
5. Pharmaceutical composition, characterized by comprising the antibody or a fragment thereof binding to the antigen, as defined in any one of claims 1 to 4, and a pharmaceutically acceptable vehicle and/or excipient.
6. An antigen-binding antibody or fragment thereof, as defined in any one of claims 1 to 4, or a pharmaceutical composition, as defined in claim 5, characterized in that it is for use in the manufacture of a medicament for the prevention or treatment of HBV infection or a disease associated with HBV infection in an individual, for use in neutralizing HBV virulence in vitro or in an individual, and/or for use in reducing serum levels of HBV DNA and/or HBsAg in an individual.
7. Antibody, according to claim 6, characterized in that the disease associated with HBV infection is hepatitis B.
8. Antibody, according to claim 6, characterized in that the individual is human.

Description

Field of invention [0001] The invention relates to the field of virology and molecular immunology, particularly to the field related to the treatment of hepatitis B virus (HBV) infection. In particular, the invention relates to an antibody (in particular, a humanized antibody) against the hepatitis B virus surface antigen (HBsAg), a nucleic acid molecule encoding the same, a method for preparing the same, and a pharmaceutical composition comprising the same. The pharmaceutical composition can be used to prevent and/or treat HBV infection or a disease associated with HBV infection (such as Hepatitis B), to neutralize HBV virulence in an individual (such as humans), or to reduce the serum level of HBV and/or HBsAg DNA in an individual. Therefore, the invention further relates to the use of the antibody (particularly a humanized antibody) and a variant thereof in the manufacture of a composition for preventing and/or treating HBV infection or a disease associated with HBV infection (such as Hepatitis B), for neutralizing HBV virulence in an individual (such as a human), or for reducing the serum level of HBV DNA and/or HBsAg in an individual. Background of the invention HBV infection, particularly chronic HBV infection, is one of the most important public health problems in the world (Dienstag JL. Hepatitis B virus infection. N Engl J Med 2008 Oct 2;359(14):1486-1500). Chronic HBV infection can cause a number of liver diseases such as chronic hepatitis B (CHB), hepatic cirrhosis (LC) and hepatocellular carcinoma (HCC) (Liaw YF, Chu CM. Hepatitis B virus infection. Lancet 2009 Feb 14; 373(9663): 582-592). It has been reported that there are approximately 2 billion people infected with HBV, and there are approximately 350 million people with chronic HBV infection worldwide now. Among these infected individuals, the risk of developing liver failure associated with HBV infection can reach as high as 15%-25%, and more than 1 million people die from these diseases each year worldwide (Dienstag JL., see above; and Liaw YF et al., see above). [0002] Currently, therapeutic agents for chronic HBV infection can be mainly classified into Interferons (IFNs) and nucleosides or nucleotide analogs (Nas) ((Dienstag JL., see above; Kwon H, Lok AS. Hepatitis B therapy. Nat Rev Gastroenterol Hepatol 2011 May; 8(5): 275-284; and Liaw YF et al., see above). The latter includes common interferon (IFN) and Peg-interferon (Peg-IFN, also called long-acting interferon), which achieves the effect of inhibiting HBV and treating HBV mainly by improving the overall immunocompetence of a patient; the latter mainly includes lamivudine (LMV), adefovir dipivoxil (ADV), Entecavir (ETV), Telbivudine (LdT) and Tenofovir, which inhibits the replication of HBV is primarily controlled by directly inhibiting HBV polymerase activity. For people infected with HBV (e.g., CHB patients), these agents, used alone or in combination therapy, have effectively inhibited viral replication in vivo and greatly reduced the level of HBV DNA; in particular, after such treatment for 52 weeks or more, the virological response rate, where the HBV DNA level is below a detection limit in patients, can reach 40-80% (Kwon H et al., see above). However, treatment with these agents alone or in combination cannot completely eliminate the HBV virus in infected individuals, and the rate of negative HBsAg conversion or serological HBsAg conversion (an indicative marker of total HBV virus elimination in patients) is generally less than 5% (Kwon H et al., see above). Therefore, it is urgent and necessary to develop new therapeutic methods and agents capable of eliminating the virus. The most effective way to eliminate the HBV virus, particularly HBsAg, is to target patients infected with HBV. [0003] One of the important research directions in this field is to develop new agents for the treatment of chronic HBV infection based on immunological means. Immunotherapy for chronic HBV infection is generally carried out in two ways, namely passive immunotherapy (corresponding to medications in the form of antibodies, etc.) and active immunotherapy (corresponding to medications in the form of vaccines, etc.). Passive immunotherapy (with antibodies as an example) refers to the process of administering a therapeutic antibody to a patient infected with HBV to prevent simple (“naive”) hepatocytes from HBV infection through antibody-mediated virus neutralization, or elimination of the virus and infected hepatocytes in vivo, by antibody-mediated immune elimination, thus achieving a therapeutic effect. Currently, polyclonal anti-HBs antibodies, obtained from serum/plasma of the immunized response with the hepatitis B vaccine, or rehabilitation from HBV infection, i.e., higher titers of hepatitis B immunoglobulin (HBIG), have been widely applied to obstruct vertical mother-to-infant transmission of HBV, prevent HBV reinfection in patients with chronic HBV infection after liver transplantation, and