HER2 Nanobody-Poly(rhamnose) Conjugates Efficiently Recruit Anti-Rhamnose Antibodies from Serum to the Surface of HER2-Expressing Cells

Recruiting endogenous antibodies to target tumor cells for elimination by the immune system represents a promising therapeutic strategy. Existing antibody-recruiting molecules (ARMs) often suffer from nonspecific binding and limited affinity for endogenous antibodies, hindering their efficacy. In this study, we developed a highly efficient and specific antibody-recruiting molecule, HER2 Nb-poly(Rha), which employs HER2 nanobodies as the cell-binding domain for enhanced recognition and binding to HER2-expressing cancer cells. Additionally, a multivalent rhamnose polymer serves as the antibody-recruiting domain. We synthesized poly(rhamnose) through RAFT polymerization, followed by the preparation of HER2 nanobody-poly(rhamnose) (HER2 Nb-poly(Rha)) using bio-orthogonal click chemistry. The resulting HER2 Nb-poly(Rha) demonstrated superior capacity in recruiting anti-rhamnose antibodies from serum compared to HER2 nanobody conjugated with monovalent rhamnose (HER2 Nb-Rha). Nanobodies, with their stability, specificity, and low immunogenicity, offer a versatile tool for targeting various disease-relevant cell surface receptors. Our approach, leveraging the multivalency of poly(rhamnose), significantly enhances the antibody-recruiting capability, showing the potential to improve the efficacy of antibody recruitment for targeted tumor cell elimination. This strategy presents a promising advancement in cancer immunotherapy by harnessing endogenous antibodies for therapeutic purposes.