Trispecific antibodies: From challenges to integration in cancer therapy

Trispecific antibodies (TsAbs) have revolutionized immunotherapy as a new approach in treating cancer patients. TsAbs antibodies fall into two categories: IgG-like, multichain molecules that possess a crystallizable fragment (Fc) region, and non-IgG-like.

They are novel engineered by Knob-into-Hole (KiH), Orthogonal Fab, and CrossMab. Trispecific antibodies exert multiple mechanisms: T-cell engagers, NK engagers, multiple tumor antigens, microenvironment modulation, and drug conjugation. They revealed, in preclinical, high efficacy with a moderate safety profile, opening doors for more integration in clinical trials. Completed and ongoing clinical studies also revealed their potent anti-tumor effect. Trispecific antibodies have advantages over other potent therapies: overcoming the monoclonal and bispecific antibodies resistance, and adoptive cellular therapies (CAR-T, TIL). However, promising results exist; trispecific antibodies face some challenges in manufacturing, immunogenicity, and mild safety issues. To potentiate the trispecific antibodies' efficacy and minimize their safety risks, some strategies are explained, including, but not limited to, novel engineering by Knob-into-Hole (KiH). Trispecific is a new era facing some challenges but featuring future promises.

The future landscape of trispecific antibodies may become new engineered antibodies like tetraspecific antibodies, combination therapies with immune checkpoint inhibitors, further investigations in solid tumors, integrating AI-driven designs, predictive and prognostic biomarkers for detecting early side effects, monitoring their efficacy, and targeting pathways like PI3K/AKT/mTOR, or RTK-RAS. These new hopes will further reshape the use of immunotherapy in treating cancer.