Engineered Nanobody Chimeras Recruits Anti-HBV Antibodies for Target Cancer Immunotherapy

The development and clinical application of monoclonal antibodies (mAbs) face challenges, including high costs, limited accessibility, and potential immunogenicity. In this study, we explored the feasibility of redirecting endogenous anti-hepatitis B virus (HBV) antibodies, generated by the HBV vaccine, toward cancer cells for immunotherapy. We engineered a bifunctional nanobody chimera, 7D12-HBsAg(99-169), which combines an anti-EGFR nanobody (7D12) and the HBV surface antigen (HBsAg) domain. The results demonstrated that nanobody chimeras effectively recruited these anti-HBV antibodies onto the cancer cell surface and triggered potent antibody-dependent cell-mediated phagocytosis and complement-dependent cytotoxicity, leading to the selective killing of EGFR-positive cancer cells. Furthermore, the 7D12-HBsAg(99-169) fusion significantly inhibited tumor growth in a xenograft mouse model by recruiting endogenous anti-HBV antibodies without inducing notable toxicity. This study establishes a proof-of-concept for leveraging endogenous antibodies induced by routine vaccination, such as those generated by HBV vaccination, for cancer immunotherapy.