Engineered neutrophil engagers overcome IgA limitations and reprogram resting neutrophils for cancer immunotherapy

BACKGROUND: Bispecific antibodies that redirect T cells or NK cells to tumors have demonstrated substantial therapeutic efficacy, but their broader application is often constrained by immune-related toxicities, limited effector cell availability, and suboptimal access to tumor sites. These challenges have prompted efforts to identify alternative effector cell types that are more abundant in circulation, readily accessible, and capable of cytotoxic activity in the tumor microenvironment. Neutrophils, which constitute the most prevalent circulating leukocyte population, represent a promising yet underutilized target for immune cell engager design. However, efforts to exploit neutrophil-mediated tumor killing through CD89 (FcαRI) have been limited by the inherent drawbacks of IgA-based formats, including poor stability, short serum half-life, and reduced developability. RESULTS: To address …