Targeting ALPPL2 with a novel CD89 bispecific antibody reprograms macrophages to enhance anti-tumor immunity.

Immunotherapy holds promise for cancer treatment, but its efficacy in solid tumors is often limited by the immunosuppressive tumor microenvironment (TME). Macrophages, abundant within the TME, can be reprogrammed to elicit anti-tumor immunity. We developed a novel bispecific antibody, ALPPL2-CD89, to specifically target and activate macrophages within the tumor. The ALPPL2-CD89 bispecific antibody demonstrated high binding affinity to both targets and significantly enhanced macrophage-mediated phagocytosis of tumor cells. In vivo studies using human CD89 transgenic mice bearing ALPPL2-expressing tumors showed significant tumor growth inhibition. Analysis of the tumor microenvironment revealed that ALPPL2-CD89 treatment increased CD3 and CD8 T cell infiltration, and shifted tumor-associated macrophages toward a pro-inflammatory M1 phenotype. Our findings establish ALPPL2-CD89 as a promising therapeutic candidate that effectively reprograms the myeloid compartment to drive potent anti-tumor immunity against ALPPL2-positive malignancies.