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KR-20260062925-A - A method for reducing hepatitis B virus surface antigen (HBsAg) and a hepatitis B drug used in the method

KR20260062925AKR 20260062925 AKR20260062925 AKR 20260062925AKR-20260062925-A

Abstract

A method for treating chronic hepatitis B infection in humans is provided, comprising the step of reducing hepatitis B surface antigen (HBsAg) in cells and blood by administering an effective amount of exogenous anti-HBs antibody or one or both of an anti-HBs antibody production vector to a subject requiring treatment, thereby providing a sustained elevated level of anti-HBs antibody in the subject.

Inventors

  • 장 용-유안

Assignees

  • 에이치비브이테크, 엘엘씨.

Dates

Publication Date
20260507
Application Date
20240606
Priority Date
20230627

Claims (20)

  1. As a method for treating chronic hepatitis B infection in humans, A method comprising the step of reducing hepatitis B surface antigen (HBsAg) in cells and blood by administering an effective amount of exogenous anti-HBs antibody or an anti-HBs antibody production vector, or both, to a subject requiring treatment, thereby providing a sustained elevated level of anti-HBs antibody in the subject.
  2. In claim 1, the reduction of HBsAg in cells and blood occurs (i) with blockade of de novo infection-mediated cccDNA supplementation, (ii) without direct inhibition of HBsAg synthesis, or (i) and (ii) with both.
  3. A method according to claim 1 or 2, wherein the anti-HBs antibody has specificity for the " a " determinant of HBsAg.
  4. In paragraph 3, the anti-HBs antibody has specificity for the human hepatocyte attachment site within the " a " determinant of HBsAg.
  5. In paragraph 4, the anti-HBs antibody blocks de novo infection by blocking HBV particles (virion and subvirus particles) from attaching to human liver cells.
  6. In claim 1, the method wherein the sustained elevated level of anti-HBs antibody is an amount of 100 mIU/ml or more for a period of 3 months or more.
  7. In paragraph 6, the method wherein the sustained elevated level of anti-HBs antibody is an amount of 1,000 mIU/ml or more for a period of 3 months or more.
  8. In claim 7, the method wherein the sustained elevated level of anti-HBs antibody is an amount of 10,000 mIU/ml or more for a period of 3 months or more.
  9. In claim 8, the method wherein the sustained elevated level of anti-HBs antibody is an amount of 100,000 mIU/ml or more for a period of 3 months or more.
  10. A method according to any one of claims 1 to 9, wherein the administration is a single or multiple administration of an exogenous anti-HBs antibody or a single administration of an anti-HBs antibody production vector.
  11. A method according to any one of claims 1 to 10, wherein HBsAg in cells and blood is reduced through the blocking of de novo infection-mediated cccDNA supplementation.
  12. In claim 12, the method is such that an effective amount of exogenous anti-HBs antibody or an anti-HBs antibody production vector is a sufficient amount to maintain a level of anti-HBs antibody to effectively and completely block de novo infection-mediated cccDNA supplementation in the presence or absence of other anti-HBV drugs.
  13. A method according to any one of claims 1 to 12, wherein the administration is the administration of an effective amount of anti-HBs antibody.
  14. A method according to any one of claims 1 to 12, wherein the administration is the administration of an effective amount of an anti-HBs antibody production vector, which provides exogenous production of anti-HBs antibodies in a subject.
  15. In claim 14, the method is a single dose administration of an anti-HBs antibody production vector in an amount of 1E11 copies or more.
  16. In paragraph 15, the method wherein a single dose of the anti-HBs antibody production vector is an amount of 2E11 copies or more.
  17. In paragraph 16, the method wherein a single dose of the anti-HBs antibody production vector is an amount of 1E12 copies or more.
  18. In paragraph 16, the method wherein a single dose of the anti-HBs antibody production vector is an amount of 3E12 copies or more.
  19. A method according to any one of claims 14 to 18, wherein the anti-HBs antibody production vector is an AAV vector selected from the group consisting of HBVZ10, HBVZ20, HBVZ30, HBVZ40, HBVZ50, HBVZ60, HBVZ70, HBVZ80, and HBVZ90.
  20. A method according to any one of claims 14 to 18, wherein the anti-HBs antibody production vector is a viral vector, a non-viral vector, or a nanoparticle.

Description

A method for reducing hepatitis B virus surface antigen (HBsAg) and a hepatitis B drug used in the method Cross-reference of related applications This application relates to U.S. Provisional Application No. 63/506,582 filed on June 6, 2023, and claims priority to it, the contents of which are incorporated herein by reference in their entirety. Statement regarding federal government-sponsored research The present invention was made with government support under Contract No. 75N930220C00042 granted by the National Institutes of Health. The U.S. government holds specific rights to the present invention. Background of the Invention Technology field The present invention relates to a method for reducing the levels of hepatitis B virus surface antigen (HBsAg) in cells and serum during chronic hepatitis B virus (HBV) infection by maintaining high levels of anti-HBs antibodies and blocking de novo infection-mediated cccDNA replenishment. Hepatitis B virus (HBV) chronically infects 316 million people worldwide, and nearly 1 million people die each year from HBV-related diseases. Current HBV drugs fail to deliver sustained inhibition of HBV replication after years of treatment, let alone provide a functional cure for HBV. Currently, both serum HBsAg markers and HBV DNA markers are required to become undetectable to establish functional treatment for HBV; that is, functional treatment for HBV is defined as undetectable serum HBsAg and HBV DNA after a limited period of HBV treatment (reference [Alter et al., Hepatology 67, 1127-1131 (2018)]). While serum HBV DNA can be inhibited and reduced to undetectable levels after long-term treatment with approved HBV drugs such as nucleoside/nucleotide analogs (NA), the most difficult challenge is finding a way to effectively reduce serum HBsAg to undetectable levels. Current strategies to reduce serum HBsAg levels involve directly inhibiting intracellular HBsAg synthesis using siRNA or antisense oligos (ASOs). However, the efficacy of these strategies and siRNA/ASO-based therapies is limited, showing an average <2 log reduction in serum HBsAg as demonstrated by both preclinical and clinical evaluations, and serum HBsAg levels return after discontinuation of therapy. Methods to demonstrate a more efficient reduction of HBsAg levels are necessary to establish effective functional treatment for HBV. The present invention discloses a method for effectively reducing HBsAg levels in cells and serum, comprising the following elements: 1. In contrast to current strategies that reduce serum HBsAg through direct inhibition of intracellular HBsAg synthesis, the method of the present invention does not require direct inhibition of intracellular HBsAg synthesis. 2. cccDNA is the major HBsAg transcription template, but it is frequently lost spontaneously in infected cells. HBV-infected cells continue to secrete HBsAg into the blood, and if the lost cccDNA pool is not replenished, this leads to the depletion of HBsAg within the infected cells. Therefore, the method of the present invention for reducing HBsAg in cells and serum aims to block de novo infection-mediated cccDNA replenishment by using sustained high levels of anti-HBs antibodies in the presence or absence of other anti-HBV drugs. 3. The present invention provides a method using an AAV-anti-HBs vector to provide sustained high levels of anti-HBs antibodies after a single infection, which can be used to block de novo infection-mediated cccDNA supplementation. The advantages of the present invention can be satisfied by a method for treating chronic hepatitis B infection in humans, either alone or in combination with the same, and The method comprises the step of reducing hepatitis B surface antigen (HBsAg) in cells and blood by administering an effective amount of exogenous anti-HBs antibody or one or both of an anti-HBs antibody production vector to a subject requiring treatment, thereby providing a sustained elevated level of anti-HBs antibody in the subject, wherein the reduction of HBsAg in cells and blood occurs (i) with the blockade of de novo infection-mediated cccDNA supplementation, (ii) without direct inhibition of HBsAg synthesis, or (i) and (ii) with both. A more complete understanding of the present invention and its many associated advantages will be readily obtained by referring to the following detailed description when considered together with the accompanying drawings, in which case: FIGS. 1a to 1d show kinetic HBsAg levels in the blood of HBV-infected uPA/SCID chimeric mice with humanized livers (days 14 to 162 post-infection), FIG. 1a shows untreated group 1 (G1); FIGS. 1b to 1d show groups 2 and 3 (G2-G4) treated with HBVZ10 and 12 weeks of entecavir, but starting at different time points to reach different HBsAg levels. HBVZ10 was administered at a dose of 2.5E11 copies on day 11 (d11) and 4E11 copies on day 58, respectively, in G2 (Fig. 1b), at a dose of 1.8E12 copies on day 22 in G3 (Fig. 1c), and at a dose of