WO2024148263A1 - Méthodes et compositions pour le traitement par anticorps d'une infection d'hépatite b - Google Patents

Méthodes et compositions pour le traitement par anticorps d'une infection d'hépatite b Download PDF

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WO2024148263A1
WO2024148263A1 PCT/US2024/010478 US2024010478W WO2024148263A1 WO 2024148263 A1 WO2024148263 A1 WO 2024148263A1 US 2024010478 W US2024010478 W US 2024010478W WO 2024148263 A1 WO2024148263 A1 WO 2024148263A1
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seq
antigen binding
binding fragment
group
antibody
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PCT/US2024/010478
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Stephen Locarnini
Aditi Deshpande
Renae WALSH
Hans Netter
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Victorian Infectious Diseases Reference Laboratory
Clearb Therapeutics Ltd.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/42—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum viral
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses

Definitions

  • the present technology relates to compositions and methods for the treatment of hepatitis B infection, including chronic hepatitis B (CHB).
  • CHB chronic hepatitis B
  • BACKGROUND [0003] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgement or admission or any form of suggestion that the prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavor to which this specification relates.
  • Hepatitis B is the most common viral hepatitis, is potentially life threatening, may have long term complications, and is one of the major public health challenges worldwide.
  • CHB infection Despite the introduction of a preventative hepatitis B vaccine more than 30 years ago, chronic hepatitis B (CHB) infection remains a global health issue (Lozano R, et al. Lancet 2012; 380(9859):2095- 128), contributing to more than 50% of the world’s liver cancer burden. Approximately one-third of individuals with chronic hepatitis B (CHB) will die from serious liver diseases, such as cirrhosis, hepatocellular carcinoma (HCC), and liver failure, if left untreated.
  • HCC hepatocellular carcinoma
  • Hepatitis B complete cure is defined by the eradication of the virus and all its replicative intermediates (Revill P, et al. Nature Reviews Gastroenterology and Hepatology, 2016, 13(4):239-248), which is presently considered an unrealistic outcome.
  • the clinical endpoint of HBsAg loss and/or seroconversion to anti-HBs is the current goal for CHB therapy, but is rarely achieved.
  • the basis for this clearance is presumably the selective pressure of an effective host antiviral (antibody driven) response.
  • the innate and adaptive immune responses in patients with CHB have been shown to be compromised, characterized by suboptimal antigen presentation, exhaustion of antigen-specific T-cells and insufficient antibody production (Wang L, et al.
  • the present disclosure provides an isolated antibody or antigen binding fragment thereof that specifically binds a hepatitis B virus (HBV) antigen, comprising: (i) three heavy chain CDR sequences comprising (a) a first heavy chain CDR selected from the group consisting of: GFTFSDF (SEQ ID NO: 13), DFWMN (SEQ ID NO: 14), and GFTFSDFW (SEQ ID NO: 15); (b) a second heavy chain CDR selected from the group consisting of: RNKPYNYQ (SEQ ID NO: 16), QIRNKPYNYQTYYSESVRG (SEQ ID NO: 17), and IRNKPYNYQT (SEQ ID NO: 18); and (c) a third heavy chain CDR selected from the group consisting of: GFDY (SEQ ID NO: 19) and TGGFDY (SEQ ID NO: 20); and (ii) three light chain CDR sequences comprising (a) a first light chain CDR selected from
  • the isolated antibody or antigen binding fragment thereof comprises a variable chain combination selected from the group consisting of: VH3 (SEQ ID NO: 8) and VL2 (SEQ ID NO: 11); VH2 (SEQ ID NO: 7) and VL1 (SEQ ID NO: 10); VH3 (SEQ ID NO: 8) and VL1 (SEQ ID NO: 10); VH1 (SEQ ID NO: 6) and VL2 (SEQ ID NO: 11); VH1 (SEQ ID NO: 6) and VL1 (SEQ ID NO: 10); VH2 (SEQ ID NO: 7) and VL2 (SEQ ID NO: 11); VH1 (SEQ ID NO: 6) and VL3 (SEQ ID NO: 12); VH3 (SEQ ID NO: 8) and VL3 (SEQ ID NO: 12); and VH2 (SEQ ID NO: 7) and VL3 (SEQ ID NO: 12).
  • the antibody or antigen Atty. Dkt. No.117586-0119 binding fragment thereof comprises a variable chain combination selected from the group consisting of: VH3 (SEQ ID NO: 8) and VL2 (SEQ ID NO: 11); VH2 (SEQ ID NO: 7) and VL1 (SEQ ID NO: 10); VH3 (SEQ ID NO: 8) and VL1 (SEQ ID NO: 10); VH1 (SEQ ID NO: 6) and VL2 (SEQ ID NO: 11); VH1 (SEQ ID NO: 6) and VL1 (SEQ ID NO: 10); VH2 (SEQ ID NO: 7) and VL2 (SEQ ID NO: 11); VH1 (SEQ ID NO: 6) and VL3 (SEQ ID NO: 12); VH3 (SEQ ID NO: 8) and VL3 (SEQ ID NO: 12); and VH2 (SEQ ID NO: 7) and VL3 (SEQ ID NO: 12).
  • the modified Fc region of the isolated antibody or antigen binding fragment thereof can interact with the modified Fc region of at least one other isolated antibody or antigen binding fragment thereof to form a multimer.
  • the composition comprises at least one antibody or antigen binding fragment thereof.
  • the composition further comprises a pharmaceutically acceptable carrier.
  • the composition further comprises a preservative.
  • the composition further comprises a co-therapeutic.
  • the co-therapeutic comprises at least one of antivirals, siRNAs, immunomodulators, and vaccines.
  • the isolated antibody or antigen binding fragment thereof further comprises (i) a variable heavy chain selected from the group consisting of: VH1 (SEQ ID NO: 6), VH2 (SEQ ID NO: 7), and VH3 (SEQ ID NO: 8); and (ii) a variable light chain selected from the group consisting of: VL1 (SEQ ID NO: 10), VL2 (SEQ ID NO: 11), and VL3 (SEQ ID NO: 12).
  • the altered biological activity comprises increased or decreased antibody half-life.
  • the modified Fc region of the isolated antibody or antigen binding fragment thereof can interact with the modified Fc region of at least one other isolated antibody or antigen binding fragment thereof to form a multimer.
  • the pharmaceutical composition comprises at least one antibody or antigen binding fragment thereof.
  • the pharmaceutical composition further comprises a preservative.
  • the pharmaceutical composition further comprises a co-therapeutic.
  • the co-therapeutic comprises at least one of antivirals, siRNAs, immunomodulators, and vaccines.
  • the pharmaceutical composition is formulated for administration intravenously, intraperitoneally, subcutaneously, or intramuscularly.
  • the isolated antibody or antigen binding fragment thereof of comprises (i) a variable heavy chain selected from the group Atty. Dkt. No.117586-0119 consisting of: VH1 (SEQ ID NO: 6), VH2 (SEQ ID NO: 7), and VH3 (SEQ ID NO: 8); and (ii) a variable light chain selected from the group consisting of: VL1 (SEQ ID NO: 10), VL2 (SEQ ID NO: 11), and VL3 (SEQ ID NO: 12).
  • the kit further comprises a co-therapeutic.
  • the co-therapeutic further comprises an antiviral, an siRNA, an immunomodulator, or a vaccine.
  • the present disclosure provides a method of measuring a hepatitis B virus (HBV) antigen in a sample comprising: (i) contacting a sample with an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises (a) three heavy chain CDR sequences comprising (1) a first heavy chain CDR selected from the group consisting of: GFTFSDF (SEQ ID NO: 13), DFWMN (SEQ ID NO: 14), and GFTFSDFW (SEQ ID NO: 15); (2) a second heavy chain CDR selected from the group consisting of: RNKPYNYQ (SEQ ID NO: 16), QIRNKPYNYQTYYSESVRG (SEQ ID NO: 17), and IRNKPYNYQT (SEQ ID NO: 18); and (3) a third heavy chain
  • the antibody or antigen binding fragment thereof comprises a variable chain combination selected from the group consisting of: VH3 (SEQ ID NO: 8) and VL2 (SEQ ID NO: 11); VH2 (SEQ ID NO: 7) and VL1 (SEQ ID NO: 10); VH3 (SEQ ID NO: 8) and VL1 (SEQ ID NO: 10); VH1 (SEQ ID NO: 6) and VL2 (SEQ ID NO: 11); VH1 (SEQ ID NO: 6) and VL1 (SEQ ID NO: 10); VH2 (SEQ ID NO: 7) and VL2 (SEQ ID NO: 11); VH1 (SEQ ID NO: 6) and VL3 (SEQ ID NO: 12); VH3 (SEQ ID NO: 8) and VL3 (SEQ ID NO: 12); and VH2 (SEQ ID NO: 7) and VL3 (SEQ ID NO: 12).
  • VH3 (SEQ ID NO: 8) and VL3 (SEQ ID NO: 12
  • FIG.1A represents the average HBsAg in each Atty. Dkt. No.117586-0119 condition over time.
  • FIG.1B shows the individual mouse data for the placebo group over time.
  • FIG.1C shows the individual mouse data for the 200 ⁇ g m4G2 group over time.
  • FIG.1D shows the individual mouse data for the 400 ⁇ g m4G2 group over time.
  • FIG.1E shows the HBcAg response in the liver of each treatment group.
  • FIGs.2A-2B show the binding affinity of murine 4G2 (m4G2) to CLB-405.
  • FIG.2A shows the binding of m4G2 to CLB-405 as measured by ELISA.
  • FIG.5A is a chart showing the average HBsAg levels for all groups.
  • FIG.5B is a chart showing the change in HBsAg levels for individual mice in the placebo group.
  • FIG.5C is a chart showing the change in HBsAg levels for individual mice in the 4G2 (3-2) 400 ⁇ g group.
  • FIG.5D is a chart showing the HBcAg response in the liver of the placebo and 4G2 (3-2) 400 ⁇ g groups.
  • FIGs.6A-6H show the effect of different treatments on HBsAg levels in persistent hepatitis B virus infection (CBA/CaJ) CHB mouse model.
  • FIG.11 is a chart showing the binding affinity results from an ELISA for the chimeric (VH+VL), 4G2-VH3+VL2, 4G2-VH2+VL1 and 4G2-VH3+VL1 antibodies.
  • DETAILED DESCRIPTION [0030] It is to be appreciated that certain aspects, modes, embodiments, variations, and features of the present technology are described below in various levels of detail in order to provide a substantial understanding of the present technology. The definitions of certain terms as used in this specification are provided below. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this present technology belongs. I.
  • anti-HBs anti-HBs antibodies
  • mAb murine
  • hAb humanized
  • antigen binding fragments thereof The antibodies include various types, including, for example, IgG.
  • the antibodies are murine or humanized.
  • the anti-HBV antibodies bind efficiently to HBV antigens.
  • the immunogenicity and therapeutic outcomes of anti-HBs mAbs are initially validated in a newly developed and validated CBA Carter J (CBA/CaJ) murine model of CHB (see, e.g., Chen HH, et al. PNAS 112(7):2175-2180 (2015)).
  • the antigen binding dynamics of the anti-HBs hAbs is initially validated using surface plasmon resonance (SPR) assays and a known HBV antigen, CLB-405 (SEQ ID NO: 40).
  • SPR surface plasmon resonance
  • CLB-405 SEQ ID NO: 40
  • the aim of anti-HBs antibodies when delivered to patients with CHB, is to accelerate and drive functional hepatitis B cure.
  • the anti-HBs antibodies can also be used to determine the presence of HBV antigens in a sample.
  • Reference to a “likelihood” of a functional cure generally means that the likelihood is 100% that the subject will reach a state of functional cure or, in the absence of circulating HBsAg, has achieved a functional cure. However, as in any biological system, variability can occur. Hence, for the purposes of the present technology, reference to a “likelihood” of a functional cure means at least 80% probability that a subject will achieve a functional cure.
  • Humanized antibodies can include full or partial fixed region amino acid sequences from one or more human antibodies and full or partial variable region amino acid Atty. Dkt. No.117586-0119 sequences from one or more non-human antibodies (e.g., mouse antibodies).
  • the humanized antibody is made by incorporating the complementarity- determining region (CDR) from one or more non-human antibodies into the non-CDR regions of one or more human antibodies.
  • Humanized antibodies can include backmutations, wherein one or more residues in a human originating fixed region is mutated to correspond to one or more residues in a non-human originating fixed region, wherein backmutations can increase binding affinity or improve other properties.
  • HBV-specific T cells During spontaneous resolution of acute hepatitis B infection, a coordinated interaction of HBV-specific T cells and B cells eliminate infected hepatocytes, suppress viral replication via non-cytolytic pathways, and neutralize virions through the production of virus-specific antibodies (anti-HBs).
  • Chronic infection represents failure of the host immune response to control HBV replication, with spontaneous clearance of HBsAg being uncommon, and found to occur in only 1-2% of patients. This rate is not enhanced with current antiviral therapies, but a key factor associated with this spontaneous loss is a low serum level of HBsAg of ⁇ 100 IU/ml (Tseng TC, et al.
  • Phase 4 is a relapse or recrudescence in liver disease activity and viral replication and this phase is also known as HBeAg-negative disease. This phase tends to eventually burn itself out and then patients often have cirrhosis.
  • the final phase, phase 5, is identified as HBsAg loss and anti-HBs seroconversion. This is also recognized as the functional cure (FC) phase.
  • FC functional cure
  • the glycosylation structure can be modified by, for example, altering component linkages and/or adding or removing mannose, N-acetylglucosamine, fucose, galactose, and/or sialic acid.
  • the Fc region of the isolated antibody, or antigen binding fragments thereof, of the present technology is modified by isotype swapping comprising pairing the Fc region of one antibody type (e.g., IgG, IgM, IgA, IgD, IgE) with the Fab region of a different antibody type.
  • No.117586-0119 treatment if any, frequency of treatment, and the nature of the effect wanted. Dosage may be singular, at an irregular interval, or at a regular interval, such as daily, weekly, or monthly.
  • the ranges of effective doses provided below are not intended to be limiting and represent exemplary dose ranges. Thus, in some embodiments, the dosage will be tailored to the individual subject, as is understood and determinable by one of skill in the art.
  • the dosage of an anti-HBs antibody for a mammalian (e.g., human) adult can be from 0.001 mg to 2,000 mg, or any range or value therein. In some embodiments, the dosage can be from 0.01 mg to 2,000 mg, or any range or value therein.
  • the dosage can be from 1,500 mg to 2,000 mg, or any range or value therein. In some embodiments, the dosage can be from 24 mg to 300 mg, or any range or value therein. In some embodiments, the dosage can be from about 2.0 mg per kg subject weight to about 40 mg per kg subject weight. VIII. Therapeutic and Antigen Measurement Methods and Kits for such Methods [0080] The following discussion is presented by way of example only, and is not intended to be limiting. Atty. Dkt. No.117586-0119 [0081] One aspect of the present technology includes methods of treating existing and/or persistent hepatitis B, including chronic hepatitis B (CHB) in a subject diagnosed as having or suspected as having a hepatitis B infection.
  • CHB chronic hepatitis B
  • kits for treating a subject in need thereof or for measuring HBV antigens in a sample wherein the kit includes the antibodies, or antigen binding fragments thereof, of the present technology.
  • a kit can optionally include other components, such as a co-therapeutic.
  • Example 1 Antibody Development and Purification
  • the murine antibody 4G2 was generated by immunizing a single BALB/c mouse with 5 doses of a pooled antigen mix, using epitopes selected from HBsAg.
  • the antigen pool was a 1:1:1 three HBsAg antigenic epitopes: a triplet of the mini-loop epitope, a triplet of the loop2 epitope, and a dimer of the extended loop1 epitope.
  • Treatment with either 200 ⁇ g or 400 ⁇ g of m4G2-IgG3 resulted in a substantial decrease in serum HBsAg levels at 4 days post treatment (W8+4 in Table 3 and FIGs.1A, 1C, 1D).
  • the decrease in serum HBsAg post- treatment was partially maintained even at 4 weeks post treatment, with the 400 ⁇ g treatment group exhibiting a stronger reduction phenotype than the 200 ⁇ g treatment group (W12+4 in Table 3 and FIGs.1A, 1C, 1D).
  • Table 3 Results of murine 4G2 (m4G2) treatment of chronic HBV [0091] These results show that serotherapy using 4G2 antibody is efficacious in the HDI CHB murine model with rapid serum HBsAg decline and clearance, and clearance of infected hepatocytes. Accordingly, these results demonstrate that the antibodies, or Atty. Dkt. No.117586-0119 antigen binding fragments thereof, of the present technology are useful in methods for treating hepatitis (HBV) infection in a subject in need thereof.
  • Example 3 Development of Humanized antibodies and CDR Identification [0092] Humanized versions of the 4G2 (h4G2) antibody were developed.
  • AD66810 siRNA was delivered subcutaneously (SC) at 3 mg/kg body weight (mpk) on study day 0.
  • Submandibular bleeds were performed at 7 days before day 0 (-7), day 7, day 14, day 24, and day 28 of the study. Samples were Atty. Dkt. No.117586-0119 assayed for serum HBsAg levels, which were then cross-compared between treatment groups to determine therapeutic efficacy.
  • each treatment was therapeutically effective in every mouse treated.
  • Treatment with anti-HBV siRNA decreased HBsAg levels at 7 days post treatment (study day 7), with antigen levels rebounding slightly throughout the remainder of the study.
  • Treatment with m4G2 decreased HBsAg levels below the limit of detection at 7 days post treatment (study day 14), with HBsAg rebounding by 17 days post treatment (study day 24).
  • FIG. 6G shows the average response in HBsAg levels for each treatment group.
  • the plate was washed 6 times with PBS, 0.05% Tween-20 and developed with 100 ⁇ l TMB substrate for 10 minutes at room temperature and stopped by adding 50 ⁇ l of stop solution.
  • the absorbance values were measured at 450 nm using a spectrophotometer.
  • the equilibrium dissociation constants (K D ) were calculated from the ratio of kd over ka.
  • the m4G2 antibody binds HBsAg, a known HBV antigen, with an EC50 of 0.2 nM as determined by ELISA (FIG.2A), and has a dissociation constant (K D ) of 14.9 nM as determined by SPR (FIG.2B).
  • the binding performance of m4G2 to CLB-405 is summarized in Table 11.
  • Table 11 4G2 binding performance to CLB-405 (SEQ ID NO: 40)
  • Example 6 Antiviral activity of multi-dose m4G2 in a hydrodynamic tail vein injection (HDI) murine model with persistent HBV infection
  • HDI hydrodynamic tail vein injection
  • HBV genotype A2adw2 plasmid into CBA/CaJ mice was performed to establish persistent infection of ⁇ 3 log IU/mL HBsAg.
  • mice were monitored at different timepoints for serological markers of HBsAg and HBV DNA.
  • FIG.3 and Table 12 multiple injections of m4G2 at 400 ⁇ g resulted in no significant HBsAg rebound up to 2 weeks post third dose in all mice in that group, and resulted in an increase in the number of mice with persistent HBsAg control from 3/8 mice in the single dose group to 5/8 in the multi dose group. Atty. Dkt.
  • Example 7 Antiviral activity of m4G2 in AAV-HBV model
  • Male C57BL/6 mice were infected with AAV8 virus carrying 1.3 copies of the HBV genome (genotype D, serotype ayw) at 5 ⁇ 10 10 viral genome equivalents to establish a stable infection of ⁇ 4 log IU/mL HBsAg.
  • Mice received two intravenous injections of m4G2 at a dose of 400 ⁇ g per mouse on days 0 and 56.
  • the efficacy of m4G2 was determined by evaluation of HBsAg in plasma at various timepoints post antibody administration.
  • the murine monoclonal antibody m4G2 binds specifically to a loop 1 epitope within the Hepatitis B surface antigen (HBsAg), and, as shown in Example 2, demonstrates anti-viral activity in the hydrodynamic tail vein Atty. Dkt. No.117586-0119 injection (HDI) mouse model of persistent HBV infection. As described in Example 3, this antibody was humanized onto human IgG1 backbone to produce the humanized 4G2 (3-2) anti-CLB-405 antibody. [0108] In vivo model.
  • the humanized candidate 4G2 (3-2) anti-CLB-405 antibody also known as 4G2-VH3+VL2
  • 4G2-VH3+VL2 was tested for efficacy in a mouse model for persistent hepatitis B virus infection (CBA/CaJ CHB mouse model).
  • a single dose of 400 ⁇ g of 4G2 (3-2) antibody was injected intravenously.
  • the CBA/CaJ CHB mouse model was developed by hydrodynamic injection (HDI) of an HBV replication competent DNA (HBV genotype A2 adw (Huang et al., “An immunocompetent mouse model for the tolerance of human chronic hepatitis B virus infection,” PNAS 103(47):17862-17867 (2006)), which allows for the delivery of DNA into hepatocytes through an intravenous tail vein injection delivery of HBV plasmid in a large aqueous volume (Yang et al., “Hydrodynamic injection of viral DNA: A mouse model of acute hepatitis B virus infection,” PNAS 99(21):13825-13830 (2002); Huang et al. (2006)).
  • HBV replication competent DNA HBV replication competent DNA
  • Table 14 shows the average reduction in HBsAg in mice treated with 4G2 (3-2) and placebo. Table 14 also shows the number of responders in each groups defined as animals with HBsAg declines >0.5 log or undetectable HBsAg.
  • Table 13 Study design to evaluate the efficacy of humanized candidate 4G2 (3-2) in persistent hepatitis B virus infection (CBA/CaJ) CHB mouse model
  • Table 14 Efficacy of humanized candidate 4G2 (3-2) by reduction in circulating HBsAg in persistent hepatitis B virus infection (CBA/CaJ) CHB mouse model [0111] Results.
  • FIGs.5A-5C show the average and individual effect of humanized candidate 4G2 (3-2) on HBsAg levels in persistent hepatitis B virus infection (CBA/CaJ) CHB mouse model.
  • FIG.5A shows the average data indicating that administration of 4G2 (3-2) resulted in decrease in serum HBsAg at 400 ⁇ g dose level showing an average 1.6 log reduction in HBsAg at week 10+4 (4 days post-dose antibody administration) where the peak efficacy was observed.
  • the HBsAg levels rebound for a subset of mice within a week with average reduction at the end of the study being 1.21 log reduction whereas on average, the placebo animals did not show significant decline in HBsAg over the duration of the study.
  • FIGs.5B and 5C show the individual data for mice in placebo and treatment groups, respectively.
  • the number of animals with undetectable HBsAg at peak response (week 10+4) was 1/8 in placebo and 8/8 in 4G2 (3-2) groups, whereas at the end of the study (week 12+4) was 1/8 in placebo and 4/8 in 4G2 (3-2) groups.
  • the number of responders (HBsAg declines >0.5 log) at peak response (week 10+4) was 1/8 in placebo and 8/8 in 4G2 (3-2) groups, whereas at the end of the study (week 12+4) was 1/8 in placebo and 7/8 in Atty. Dkt. No.117586-0119 4G2 (3-2) groups.
  • the humanized candidate 4G2 demonstrated liver clearance as assessed by IHC of Hepatitis B core antigen (HBcAg) positive cells in the liver.
  • HBV Hepatitis B core antigen
  • Example 9 Humanized 4G2 is effective in combination with siRNA in the HDI CHB model
  • Humanized 4G2 (h4G2) candidates in combination with anti-HBV siRNA were assayed for their efficacy in inducing a response in a mouse model for persistent hepatitis B virus infection (CBA/CaJ CHB mouse model).
  • HBV replication competent DNA plasmid HBV genotype A2 adw (PJ Chen)
  • HBV genotype A2 adw PJ Chen
  • a single HDI of an HBV replication competent DNA plasmid has generally been shown to induce persistent HBV replication (> 6 months).
  • HDI HBV DNA and HBsAg serological markers were measured in mouse serum to confirm that a persistent HBV infection was established.
  • Mice with a persistent HBV replication were then used to evaluate the effectiveness of humanized 4G2 in combination with siRNA treatment.
  • HBV model mice either received a placebo, siRNA treatment (AD-66810), or combination treatment with siRNA (AD-66810) and h4G2-VH3+VL2, with 3 mg/kg (mpk) siRNA administered at day 0 subcutaneously (SC) and 400 ⁇ g h4G2-VH3+VL2, or an equivalent volume of placebo PBS, administered at day 7 intravenously (IV).
  • Table 15 Humanized 4G2 and siRNA experimental design [0115] As shown in FIGs.7A-7D, combination treatment with anti-HBV siRNA and h4G2-VH3+VL2 resulted in synergistic beneficial effects. At day -7 all treatment groups Atty. Dkt.
  • Antibody treatment combined with siRNA treatment further exhibited synergistic therapeutic effects in a persistent HBV model, including combination treatment with h4G2- VH3+VL2 and anti-HBV siRNA.
  • these results demonstrate that the antibodies, or antigen binding fragments thereof, of the present technology are useful in methods for treating hepatitis (HBV) infection in a subject in need thereof.
  • Example 10 Binding Affinity Analysis of h4G2 Candidates.
  • the top three humanized 4G2 candidates demonstrating the greatest binding affinity (4G2-VH3+VL2, 4G2-VH2+VL1, and 4G2-VH3+VL1), as described in Example 3, were purified at 20 mg scale with > 95% purity (FIG.8), and were further analyzed by multi-dose SPR and ELISA to confirm binding affinity to Hepatitis B antigens.
  • the selected antibodies were evaluated for binding to CLB-405 HBsAg using a Surface Plasmon Atty. Dkt. No.117586-0119 Resonance (SPR) biosensor, Biacore 8K (GE Healthcare).
  • Antibodies were captured on the sensor chip through Fc capture method and CLB-405 HBsAg was used as the analyte (FIG. 9).
  • the data of dissociation (kd) and association (ka) rate constants were obtained using Biacore 8K evaluation software.
  • the equilibrium dissociation constants (KD) were calculated from the ratio of kd over ka.
  • 1 ⁇ g/ml CLB-405 was coated on an ELISA plate in 100 ⁇ l CBS at 4°C overnight. The washed and blocked plates were incubated with the selected antibodies titrated 3-fold starting at 15 ⁇ g/ml.
  • the plates were washed and incubated with anti-Human IgG Fc [HRP] and anti-Mouse Fc [HRP] for 30min at 37°C.
  • the plate was washed and developed with TMB substrate at room temperature and stopped by addition of stop solution.
  • the absorbance values were measured at 450 nm using a spectrometer.
  • each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc.
  • all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above.
  • a range includes each individual member.
  • a group having 1-3 cells refers to groups having 1, 2, or 3 cells.
  • a group having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so forth.
  • Atty. Dkt. No.117586-0119 All patents, patent applications, provisional applications, and publications referred to or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification.
  • Hepatitis B surface antigen S (HBsAg-S) protein (external loop region between 100 and 160 amino acid position is underlined, stop codon is *): MENITSGFLGPLLVLQAGFFLLTRILTIPQSLDSWWTSLNFLGGTTVCLGQNSQSPT SNHSPTSCPPTCPGYRWMCLRRFIIFLFILLLCLIFLLVLLDYQGMLPVCPLIPGSS TTSTGPCRTCMTTGQGTSMYPSCCCTKPSDGNCTCIPIPSSWAFGKFLWEWASARFS WLSLLVPFVQWFVGLSPTVWLSVIWMMWYWGPSLYSILSPFLPLLPIFFCLWVYI* (SEQ ID NO: 3) Hepatitis B surface antigen S (HBsAg-S) protein and a FLAG tag (FLAG sequence is italicized and external loop region between 100 and 160 amino acid position is underlined): MDYKDDDDKENITSGFLGPLLVLQAG
  • Humanized variable heavy chain CDR1 IMGT GFTFSDFW (SEQ ID NO: 15) Humanized variable heavy chain CDR2 Chothia: RNKPYNYQ (SEQ ID NO: 16) Humanized variable heavy chain CDR2 Kabat: QIRNKPYNYQTYYSESVRG (SEQ ID NO: 17) Humanized variable heavy chain CDR2 IMGT: IRNKPYNYQT (SEQ ID NO: 18) Humanized variable heavy chain CDR3 Chothia: GFDY (SEQ ID NO: 19) Humanized variable heavy chain CDR3 Kabat: GFDY (SEQ ID NO: 19) Humanized variable heavy chain CDR3 IMGT: TGGFDY (SEQ ID NO: 20) Humanized variable light chain CDR1 Chothia: KASQDVSSDVA (SEQ ID NO: 21) Humanized variable light chain CDR1 Kabat: KASQDVSSDVA (SEQ ID NO: 21) Humanized variable light chain CDR1 IMGT: Q

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Abstract

Sont divulguées dans la présente invention des compositions et des méthodes pour le traitement d'une infection d'hépatite B, notamment l'hépatite B chronique (HBC).
PCT/US2024/010478 2023-01-06 2024-01-05 Méthodes et compositions pour le traitement par anticorps d'une infection d'hépatite b WO2024148263A1 (fr)

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US202363588082P 2023-10-05 2023-10-05
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110240658A (zh) * 2019-06-20 2019-09-17 徐州医科大学 靶向hbv治疗肝癌的car-t及其应用
US20190389939A1 (en) * 2015-10-09 2019-12-26 Xiamen University Antibody against hepatitis b surface antigen and use thereof
US20220119537A1 (en) * 2012-05-18 2022-04-21 Amgen Inc. St2 antigen binding proteins
US20220127336A1 (en) * 2018-12-19 2022-04-28 Humabs Biomed Sa Antibodies that neutralize hepatitis b virus and uses thereof
WO2022240159A1 (fr) * 2021-05-10 2022-11-17 메디맵바이오 주식회사 Anticorps anti-tigit et leur utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220119537A1 (en) * 2012-05-18 2022-04-21 Amgen Inc. St2 antigen binding proteins
US20190389939A1 (en) * 2015-10-09 2019-12-26 Xiamen University Antibody against hepatitis b surface antigen and use thereof
US20220127336A1 (en) * 2018-12-19 2022-04-28 Humabs Biomed Sa Antibodies that neutralize hepatitis b virus and uses thereof
CN110240658A (zh) * 2019-06-20 2019-09-17 徐州医科大学 靶向hbv治疗肝癌的car-t及其应用
WO2022240159A1 (fr) * 2021-05-10 2022-11-17 메디맵바이오 주식회사 Anticorps anti-tigit et leur utilisation

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