Safety and Antiviral Activity of a Monoclonal Hepatitis B Antibody (The SAMBA Study)

Along with persistence of viral antigens, impaired HBV-specific immunity contributes to chronicity of infection. Chronic HBV (CHB) is characterized by depletion or functional impairment of HBV-specific T cells, resulting in defective proliferation and cytokine production, as well as impaired production of antibodies against HBsAg, with an expansion of atypical memory B cells. The importance of host immunity for HBV clearance is well recognized, but the critical immunological events required to achieve functional cure are not fully understood. Persistent high HBsAg levels along with dysfunctional immunity has raised the possibility that HBsAg itself is immunoregulatory in HBV infection. Chronic exposure to high levels of HBsAg may render HBV-specific T cells overly activated and functionally tolerated. Thus, decreasing serum HBsAg could be a valuable therapeutic strategy, due to its potential to alleviate functional exhaustion and confer immune control.

In parallel, antibodies to HBsAg are associated with successful vaccination and recovery from acute infection. Indeed, a difference between chronically infected and naturally recovered individuals is a robust polyclonal B cell response to HBsAg. Whether these associations reflect an etiologic role for anti-HBV neutralizing antibodies is not known. However, depletion of antibody producing B lymphocytes in CHB patients by rituximab is associated with HBV reactivation, indicating that B cells or their antibody products are playing a significant role in controlling the infection. The only immunomodulatory therapy currently available to treat CHB, IFN-α, is effective in only 30% of people, with marked differences observed across HBV genotypes being most effective against HBV genotype A and B infections.New therapeutic strategies that interfere with viral persistence and ongoing immune dysregulation with the goal to achieve a functional cure are needed. Several strategies are in clinical development including antiviral (e.g.small interfering RNA) (siRNA) and nucleic acid polymers (NAPs), and immune restoration approaches (e.g. therapeutic vaccination, toll-like receptor agonists, checkpoint blockade inhibitors and passive immunotherapy with anti-HBs antibodies).

Antibodies are among the key modulators of immunity and are uniquely attractive pharmaceutical agents because of their dual functionality. In addition to targeting a specific epitope with their variable domains, antibodies differ from direct antivirals in that they can recruit immune effector functions through their Fc domains. In addition to accelerating clearance of viruses andinfected cells through phagocytosis or direct cellular cytotoxicity, antigen-antibody immune complexes are also potent immunogens that can foster development of host immune responses. For example, antibody-based cancer therapies eliminate malignant cells and induce adaptive T cell immunity, and have dramatically increased the number of individuals that control and survive malignant diseases. Whether the same concepts are applicable to the management of chronic viral infections is an area of active investigation, particularly in the HIV-1 field.

In CHB, antibodies have the potential to enhance clearance of HBsAg. Although studies in transgenic animals indicate that T cell tolerance to HBsAg is durable and difficult to reverse, the models are not entirely reflective of human infection.

Whether antibody therapy can restore some aspects of HBV-specific T cell immunity in humans has not been determined. Immunotherapy with HBsAg-specific antibodies has shown some direct HBsAg suppression effects in clinical studies. However, the HBsAg antibodies that were evaluated only led to short term decline in HBsAg levels in CHB patients, that were very similar to the effects of treatments based on hepatitis B immune globulin (HBIG). More potent antibodies with long-lasting effects on circulating HBsAg and potential to modulate and restore HBV-specific immune responses are needed to evaluate the role of immunotherapy in CHB treatment and remission.

This study aims to evaluate the safety, maximal tolerated dose, pharmacokinetics (PK) and antiviral effects of a highly potent neutralizing human monoclonal antibody (mAb), HepB mAb19, that targets HBV S-protein in individuals with CHB. Safety, PK and virologic data generated by this study will guide the selection of a dosing regimen for subsequent multidose studies in individuals with CHB, in combination with standard HBV antiviral therapy and/or other investigational products, including other anti-HBs mAbs.

HepB mAb19 is a human mAb of Immunoglobulin G (IgG) 1kappa isotype that specifically binds to the "a" determinant of the extracellular loop of the HBV surface antigen (HBsAg). HepB mAb-19 was isolated and cloned from an HBsAg vaccinated individual at the Rockefeller University. The naturally occurring antibody was modified by two one-amino acid substitutions. These substitutions enhance the antibody binding affinity to the neonatal Fc receptor, prolonging its half-life in vivo, but do not interfere with antigen binding or with affinity to Fc gamma receptors.

To assess the efficacy of anti-HBV antibodies in vivo, researchers used human liver chimeric FNRG mice, which can sustain HBV infection. They tested two antibodies, HepB mAb20 and HepB mAb07, as pre-exposure prophylaxis. Both antibodies successfully prevented HBV infection in these mice, while all control mice became infected. In mice with established HBV infections, HepB mAb20, HepB mAb07, and HepB mAb19 stabilized viremia but did not eliminate it entirely. Over time, some mice treated with mAb20 and mAb07 developed an increase in viremia, attributed to the emergence of the G145R escape mutation. Notably, HepB mAb19 did not lead to such escape mutations, suggesting higher resistance.

Further, combination therapies targeting different viral epitopes were evaluated. While a HepB mAb06 + HepB mAb07 combination showed partial resistance to escape mutations, it still allowed the emergence of mutations. In contrast, combinations such as HepB mAb17 + HepB mAb19 and a triple therapy (HepB mAb16, HepB mAb17, HepB mAb19) successfully controlled viremia and prevented escape mutations. These findings indicate that monotherapy may lead to escape mutations, while well-chosen antibody combinations can improve viral control, potentially enhancing immune response during antiviral therapy

A GLP-compliant study on HepB mAb19 tested cross-reactivity in normal human and rat tissues, revealing limited cytoplasmic binding in specific cells, mainly in acinar epithelial cells in human salivary glands and various rat tissues. Since the binding was cytoplasmic, it is unlikely to have toxicological significance. A 25-day toxicology study in rats (doses 0, 4, 15, or 60 mg/kg IV) showed no adverse effects or significant changes in clinical or lab parameters, establishing the no-observed-adverse-effect-level (NOAEL) at 60 mg/kg. HepB mAb19 showed dose-proportional peak concentration and stable half-life of 13-16 days, with a 4-fold exposure increase upon repeated dosing.

Our hypothesis is that intravenous administration of HepB mAb19 during suppressive nucleos(t)ide therapy will be safe and well tolerated, will lead to decreased levels of circulating HBsAg, and enhance host innate and adaptive immune responses to HBV.

The study has two parts:

Part A: In part A, a single dose of HepB mAb19 or placebo is administered by randomization into three different dose groups. Gradually higher doses of HepB mAb19 will be used, meaning that participants in group 1 will receive a low dose (3 mg/kg), which will be assessed for safety before a single dose of 10 mg/kg and 30 mg/kg are tested under the same principle. Participants in each group 1-3 will be randomized in a 3:1 ratio to receive either HepB mAb19 or placebo (normal saline).

Part B: Based on part A, the maximum tolerated dose (MTD) of HepB mAb19 will be established. This dose will subsequently be used in part B, where a fourth group of 18 individuals will receive HepB mAb19 without randomization.

Participants will undergo safety assessments 1, 3, and 7 days after the administration of the trial antibody or placebo infusion, then weekly through to week 4, and finally at weeks 8, 12, 24, 36, and 48.

Blood samples will be collected during study visits. These blood samples will be used for analyses of safety, how HepB mAb19 is absorbed in the body, the effects of HepB mAb19 on HBV, and the immune system's response to it. Blood samples will be collected on day 0 before the administration of HepB mAb19, at the end of the antibody or placebo infusion, after 1, 3, and 7 days, and during subsequent follow-up visits.