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EP-4735477-A2 - METHODS FOR REDUCING HEPATITIS B VIRUS SURFACE ANTIGEN (HBSAG) AND DRUGS USED IN THE METHODS THEREOF

EP4735477A2EP 4735477 A2EP4735477 A2EP 4735477A2EP-4735477-A2

Abstract

A method of curing chronic hepatitis B infection in humans is provided, the method including administering to a subject in need thereof, an effective amount of one or both of an exogenous anti-HBs antibody or an anti-HBs antibody producing vector to reduce cellular and blood hepatitis B surface antigen (HBsAg), by providing a sustained elevated level of anti-HBs antibody in the subject.

Inventors

  • ZHANG, Yong-yuan

Assignees

  • HBVtech LLC

Dates

Publication Date
20260506
Application Date
20240606

Claims (20)

  1. 1. A method of curing chronic hepatitis B infection in humans, comprising: administering to a subject in need thereof, an effective amount of one or both of an exogenous anti-HBs antibody or an anti-HBs antibody producing vector to reduce cellular and blood hepatitis B surface antigen (HBsAg), by providing a sustained elevated level of anti-HBs antibody in the subject.
  2. 2. The method of claim 1, wherein the reduction of cellular and blood HBsAg occurs (i) with blocking of de novo infection mediated cccDNA replenishment or (ii) without direct inhibition of HBsAg synthesis, or both (i) and (ii).
  3. 3. The method of one of claims 1 or 2, wherein the anti-HBs antibody has specificity against the “a” determinant of HBsAg.
  4. 4. The method of claim 3, wherein the anti-HBs antibody has specificity against human hepatocyte attachment site in the a determinant of HBsAg.
  5. 5. The method of claim 4, wherein the anti-HBs antibody blocks de novo infection through blocking HBV particles (virions and subviral particles) from attaching to human hepatocytes.
  6. 6. The method of claim 1 , wherein the sustained elevated level of anti-HBs antibody is an amount of 1 OOmlU/ml or higher for a period of 3 months or longer.
  7. 7. The method of claim 6, wherein the sustained elevated level of anti-HBs antibody is an amount of l,000mIU/ml or higher for a period of 3 months or longer.
  8. 8. The method of claim 7, wherein the sustained elevated level of anti-HBs antibody is an amount of 10,000mIU/ml or higher for a period of 3 months or longer.
  9. 9. The method of claim 8, wherein the sustained elevated level of anti-HBs antibody is an amount of 100,000 mIU/ml or higher for a period of 3 months or longer.
  10. 10. The method of any one of claims 1 to 9, wherein the administration is a single or multiadministration of the exogenous anti-HBs antibody or a single administration of the anti-HBs antibody producing vector.
  11. 11. The method of any one of claims 1 to 10. wherein cellular and blood HBsAg is reduced through blocking of de novo infection mediated cccDNA replenishment.
  12. 12. The method of claim 12, wherein the effective amount of exogenous anti-HBs antibody or an anti-HBs antibody producing vector is an amount to maintain a level of anti-HBs antibody sufficient to effectively and completely block de novo infection mediated cccDNA replenishment in the presence of or absence of other anti-HBV drugs.
  13. 13. The method of any one of claims 1 to 12, wherein the administration is administration of an effective amount of the anti-HBs antibody.
  14. 14. The method of any one of claims 1 to 12, wherein the administration is administration of an effective amount of the anti-HBs antibody producing vector, which provides an endogenous production of anti-HBs antibody in the subject.
  15. 15. The method of claim 14, wherein the administration is a single dose administration of the anti-HBs antibody producing vector, in an amount of 1E11 copies or more.
  16. 16. The method of claim 15, wherein the single dose administration of the anti-HBs antibody producing vector is in an amount of 2E11 copies or more.
  17. 17. The method of claim 16, wherein the single dose administration of the anti-HBs antibody producing vector is in an amount of 1E12 copies or more.
  18. 18. The method of claim 16, wherein the single dose administration of the anti-HBs antibody producing vector is in an amount of 3E12 copies or more.
  19. 19. The method of any one of claims 14 to 18, wherein the anti-HBs antibody producing vector is an AAV vector selected from the group consisting of HBVZ10, HBVZ20, HBVZ30, HBVZ40, HBVZ50, HBVZ60, HBVZ70, HBVZ80, and HBVZ90.
  20. 20. The method of any one of claims 14 to 18, wherein the anti-HBs antibody producing vector is a viral vector, a non- viral vector, or a nanoparticle.

Description

TITLE OF THE INVENTION TITLE METHODS FOR REDUCING HEPATITIS B VIRUS SURFACE ANTIGEN (HBsAg) AND THE HEPATITIS B DRUGS USED IN THE METHODS THEREOF CROSS REFERENCE TO RELATED APPLICATIONS [0001] The present application is related to, and claims priority to, U.S. Provisional Application No. 63/506,582, fded June 6, 2023, the contents of which are hereby incorporated by reference in their entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH [0002] This invention was made with government support under contract no. 75N930220C00042 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND OF THE INVENTION FIELD OF THE INVENTION [0003] The present invention relates to methods for reducing cellular and serum hepatitis B virus surface antigen (HBsAg) levels in chronic hepatitis B virus (HBV) infections by maintaining high anti-HBs antibody levels and blocking de novo infection mediated cccDNA replenishment. DESCRIPTION OF THE RELATED ART [0004] Hepatitis B virus (HBV) has chronically infected 316 million people worldwide and nearly one million die of HBV related diseases each year. Current HBV drugs rarely deliver durable suppression of HBV replication after years of medication, let alone HBV functional cure. [0005] Currently, both serum HBsAg and HBV DNA markers are required to become undetectable in establishing HBV functional cure, that is, HBV functional cure is defined as undetectable serum HBsAg and HBV DNA after a finite period of HBV treatment (Alter et al., Hepatology 67 , 1127-1131 (2018)). Serum HBV DNA can be inhibited and reduced to undetectable level after long-term treatment with the approved HBV drug of nucleos/tide analogues (NA) but the most difficult challenge is how to effectively reduce serum HBsAg to undetectable level. [0006] The current strategy to reduce serum HBsAg level is to directly inhibit intracellular HBsAg synthesis with siRNA or antisense oligos (ASO) drugs. However, the efficacy of this strategy and siRNA/ASO based therapies is limited, showing average <2 log reduction in serum HBsAg demonstrated by both preclinical and clinical evaluations and serum HBsAg level bounces back after stopping the therapy. [0007] A method that demonstrates more efficient reduction of HBsAg level is needed for establishing an effective HBV functional cure. SUMMARY OF THE INVENTION [0008] This invention discloses how to effectively reduce cellular and serum HBsAg level and it comprises following elements: [0009] 1. In contrast to the current strategy to reduce serum HBsAg through direct inhibition of intracellular HBsAg synthesis, the present invention method does not require a direct inhibition of intracellular HBsAg synthesis. [0010] 2. cccDNA is the major HBsAg transcription template but is frequently spontaneously lost in infected cells. HBV infected cells keep secreting HBsAg into blood, leading to emptying HBsAg in the infected cells if the lost cccDNA pool does not get replenished. Thus, the present invention method of reducing cellular and serum HBsAg aims to block de novo infection mediated cccDNA replenishment using sustained high level of anti-HBs antibody in the presence or absence of other anti-HBV drugs. [0011] 3. The present invention provides the method for using AAV-anti-HBs vectors to express sustained high levels of anti-HBs antibody after a single injection and can be used to block de novo infection mediated cccDNA replenishment. [0012] The advantages of the present invention, either alone or in combinations thereof, may be satisfied by method of curing chronic hepatitis B infection in humans, comprising: administering to a subject in need thereof, an effective amount of one or both of an exogenous anti-HBs antibody or an anti-HBs antibody producing vector to reduce cellular and blood hepatitis B surface antigen (HBsAg), by providing a sustained elevated level of anti-HBs antibody in the subject, wherein the reduction of cellular and blood HBsAg occurs (i) with blocking of de novo infection mediated cccDNA replenishment or (ii) without direct inhibition of HBsAg synthesis, or both (i) and (ii). BRIEF DESCRIPTION OF THE DRAWINGS [0013] A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings, wherein: [0014] FIGS. 1A-1D show kinetic HBsAg levels in blood of HBV infected uPA/SCID chimeric mice with humanized livers (from day 14 to day 162 post infection), wherein Figure 1A shows Group 1 (Gl) without treatment; Figure 1B-1D represent where Groups 2 and 3 (G2-G4) were treated with HBVZ10 and 12-weeks of entecavir but started at different timepoints to allow HBsAg to reach different levels. HBVZ10 was given at day 11 (dl l) at a dose of 2.5E11 copies and day 58 at a dose of 4E11 copies, respectively in G2 (Figure IB), given a