Bispecific antibodies: current advances and future perspectives

Abstract

Bispecific antibodies (BsAbs) are emerging immunotherapeutics that simultaneously engage two distinct targets. This property provides unique mechanisms of action that are not achieved by conventional monoclonal antibodies, including cell-cell bridging, modulation of multiple signaling pathways, and recruitment of diverse immune effector cells. Among these approaches, T cell-engaging BsAbs are the most established modality. By simultaneously targeting a tumor-associated antigen and CD3 on T cells, they promote tumor–T cell bridging, immune synapse formation, and MHC-independent T cell activation, and have shown marked clinical efficacy in several hematologic malignancies. More recently, their application has been extended to solid tumors, supported by encouraging data from clinical trials. Despite these advances, the efficacy and safety of BsAbs face several limitations, including short half-lives, tumor antigen escape, off-tumor toxicity, and insufficient T cell activation due to the lack of costimulatory signals. To address these obstacles, BsAb structures have been modified in various ways, including Fc fusion, multispecific targeting, and armored designs that enhance T cell function. These approaches aim to improve pharmacokinetics, specificity, and antitumor efficacy.

In addition to these efforts, novel delivery platforms have been developed to further enhance the therapeutic potential of BsAbs. Engineered extracellular vesicles and nanoparticle-based systems may improve pharmacokinetics and tumor delivery, while enabling the integration of additional functional molecules beyond conventional BsAb formats. In this review, we summarize the basic principles of BsAbs, highlight key clinical developments, and discuss emerging strategies and remaining challenges in the development of next-generation BsAbs.