The engineered monoclonal antibody tobevibart enhances HBsAg capture by Fc receptor positive cells leading to activation of HBV-specific T cells
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Background & Aims
Immune targeting is likely required for 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, FcγR reporter cells, and primary human or mouse immune cells to assess HBsAg binding, 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 mediated gain of function in FcγR signaling in immune complexes (ICs) with HBsAg compared to wild-type (WT) Fc and increased binding of HBsAg to neutrophils and monocytes in vitro . Similarly, dosing of 300 mg tobevibart in patients with CHB mediated binding of HBsAg to these cells in vivo , concomitant with reducing HBsAg in circulation. 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, ICs of HBC34*-GAALIE and HBsAg activated DCs from mice transgenic for human FcγRs and stimulated CD4+ T cells from immunized animals more than ICs with HBC34*-WT.
Conclusions
We demonstrate that tobevibart combines the advantages of potent neutralization of HBV and HDV, FcγR-mediated reduction of HBsAg, and Fc-dependent enhancement of T cell responses. Tobevibart is currently 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
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 show that the engineered Fc region of tobevibart effectively interacted with several immune cell types in vitro , which may support the rapid removal of damaging virus proteins from circulation, potentially activating T cell responses that may control HBV infection long term.
