Chemical‐Assembled Macrophage‐Engaging Glypican‐3 × Signal Regulatory Protein‐α (SIRP‐α) Bispecific Antibody for Immunotherapy Against Liver Cancer

ABSTRACT Bispecific antibodies (BsAbs) represent a growing class of cancer immunotherapeutics, yet their wider adoption remains limited by complex recombinant production and limited manufacturing efficiency. Here, we report a chemically assembled macrophage‐engaging glypican‐3 × signal regulatory protein‐α (SIRP‐α) bispecific antibody for the treatment of liver cancer. Using our bifunctional linker, glypican‐3‐binding peptide dimers were conjugated to a native anti‐SIRP‐α IgG via a rapid one‐pot, two‐step process, yielding a novel dendritic bispecific antibody (dBsAb). Such a construct simultaneously targets glypican‐3‐positive hepatocellular carcinoma cells and blocks the CD47–SIRP‐α axis, thereby promoting macrophage engagement and phagocytosis. In vitro studies showed substantially enhanced macrophage adhesion and tumor cell clearance compared with the monoclonal antibody. In an in vivo experiment, dBsAb demonstrated a 68% reduction in tumor growth, with increased macrophage infiltration, M1 polarization, and elevated antigen presentation without observable systemic toxicity. This chemical assembly approach offers a practical alternative to recombinant methods for constructing bispecific antibodies and may facilitate the development of macrophage‐directed immunotherapies.