Engineered monoclonal antibody tobevibart enhances HBsAg capture by Fc receptor-positive cells and activates HBV-specific T cells

Abstract

Background & aims: Effective immune targeting is likely essential for achieving functional cure of chronic hepatitis B (CHB). Tobevibart, a human monoclonal antibody against hepatitis B surface antigen (HBsAg), neutralizes HBV and HDV. This study aimed to characterize the effects of the engineered GAALIE Fc of tobevibart on HBV immune responses.

Methods: We studied tobevibart and its equivalent, HBC34^∗-GAALIE, in vitro using electron microscopy, reporter cells, and primary human or mouse immune cells to assess dynamics of HBsAg reduction, dendritic cell (DC) activation, and T-cell stimulation. Tobevibart-mediated binding of HBsAg to immune cells was also evaluated in a phase I clinical trial in patients with CHB.

Results: The GAALIE Fc of tobevibart increased binding to activating FcγRs, decreased binding to inhibitory FcγRIIb, mediated gain of function in FcγR signaling in immune complexes with HBsAg, and increased binding of HBsAg to neutrophils and monocytes in vitro compared to wild-type Fc. Similarly, administration of 300 mg tobevibart in patients with CHB resulted in binding of HBsAg to these cells in vivo, concurrent with a reduction in circulating HBsAg. In vitro, immune complexes of HBC34^∗-GAALIE and HBsAg activated human DCs significantly more than HBC34^∗-wild-type. These DCs presented antigen and stimulated HBsAg-specific human T cells. Similarly, HBC34^∗-GAALIE augmented HBsAg-specific CD4⁺ T-cell responses from mice transgenic for human FcγRs.

Conclusions: We demonstrate that tobevibart combines the advantages of potent neutralization of HBV and HDV with FcγR-mediated reduction of HBsAg and enhancement of T-cell responses. It is currently under clinical investigation, alone and in combination with other agents, for the treatment of chronic hepatitis delta and to induce functional cure of CHB.

Clinical trial: VIR-3434-1002, phase 1, ClinicalTrials.gov identifier NCT04423393.

Impact and implications: Chronic infection with HBV or co-infection with HDV can cause severe liver disease and cancer. We have previously shown that the monoclonal antibody tobevibart potently neutralizes HBV and HDV. Here we demonstrate that the engineered Fc region of tobevibart effectively interacted with several immune cell types, potentially facilitating the rapid removal of damaging viral proteins from the circulation and activating T-cell responses that may control HBV infection long term.

Keywords: FcγR activation; HBsAg; Hepatitis B virus (HBV); T cells; anti-HBs; chronic infection; dendritic cells; human monoclonal antibody (mAb); immune complex.