T cell–activating bispecific antibodies in cancer therapy

Effector lymphocytes are multifunctional cells of the immune system that promote cytolysis of pathogen-infected cells and nascent tumors. Tumors must learn to evade effectors and employ a wide variety of mechanisms to do so. Bispecific Abs (BsAbs) are an emerging cancer immunotherapy approach seeking to re-engage either T effectors or NK cells with malignant cells. Possessing specificity for effector cells on one end and a tumor Ag on the other, these molecules work by attracting effectors to the target cell to build an immunologic synapse and induce tumor cell killing. The BsAb blinatumomab, for example, has specificity for the T cell–activating cell surface protein CD3 and the B cell Ag CD19. The only BsAb with regulatory approval currently, blinatumomab is used in the treatment of relapsed or refractory B cell acute lymphoblastic leukemia. Many additional BsAbs are in preclinical development, however, targeting many different tumor types. The variety of potential effector cells and cancer Ags, along with potential combination therapies, make BsAbs an active area of drug development. In this review, we discuss cancer recognition by the immune system and structural and mechanistic aspects of BsAbs. We summarize key steps in preclinical development and subsequent translation to medical practice. Future directions for BsAbs include combinations with a wide variety of both immunologic and nonimmunologic therapies. Defining their optimum clinical use is at early stages.