Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

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 virus (HBV) surface antigen (HBsAg), neutralizes HBV and hepatitis delta virus (HDV). This study aimed to characterize 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 evaluated also in a phase 1 clinical trial in patients with CHB. RESULTS: The GAALIE Fc of tobevibart increased binding to activating FcgammaRs, decreased binding to inhibitory FcgammaRIIb, mediated gain of function in FcgammaR signaling in immune complexes (ICs) with HBsAg, and increased binding of HBsAg to neutrophils and monocytes in vitro compared to wild-type (WT) 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, ICs of HBC34*-GAALIE and HBsAg activated human DCs significantly more than HBC34*-WT. 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 FcgammaRs. CONCLUSIONS: We demonstrate that tobevibart combines the advantages of potent neutralization of HBV and HDV with FcgammaR-mediated reduction of HBsAg and enhancement of T cell responses. Tobevibart is under clinical investigation alone or in combination with other agents to treat patients with chronic hepatitis delta and to induce functional cure of patients with CHB. IMPACT AND IMPLICATIONS (LAY SUMMARY): Chronic infection with hepatitis B virus (HBV) or co-infection with hepatitis delta virus (HDV) can cause severe liver disease and cancer. We previously showed 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 circulation and activating T cell responses that may control HBV infection long term. CLINICAL TRIAL: VIR-3434-1002, phase 1, ClinicalTrials.gov identifier NCT04423393.