Molecular engineering and clinical translation of T cell engaging bispecific antibodies in cancer therapy

Abstract Bispecific T-cell engagers are Fc-less, Fv-based members of the broader family of T-cell-engaging bispecific antibodies designed to redirect cytotoxic T cells toward tumor cells by simultaneously binding CD3 and tumor-associated antigens. Despite their clinical promise, CD3-engaging bispecific antibody therapies remain limited by cytokine release syndrome (CRS), a systemic inflammatory response triggered by excessive immune activation, and, in the case of canonical Fc-less BiTEs, by short serum half-life. Half-life extension strategies, including Fc- or albumin-based engineering and FcRn-mediated recycling, have therefore become central to next-generation construct design. This review consolidates recent developments in CD3-engaging bispecific antibody engineering, including format optimization, affinity modulation, selectivity enhancement, and half-life prolongation, as well as clinical applications in hematologic and solid malignancies. Toxicity management strategies, including step-up dosing, corticosteroid premedication, and tocilizumab-based CRS management, are emphasized, together with emerging biomarkers that may predict response and adverse events. Furthermore, future directions, including trispecific antibodies, BiTE-CAR hybrids, tumor-selective activation through logic-gated or conditional binding strategies, and biomarker-guided patient selection, are discussed. This article integrates engineering innovations with clinical outcomes and translational challenges to guide the development of next-generation T-cell-engaging bispecific therapeutics.