Agonistic bispecific antibodies: an emerging frontier in antibody therapeutics

Antibody-based cancer therapies have long been valued for their high target specificity and favorable safety profiles compared with conventional chemotherapy and radiotherapy. The field has expanded rapidly, driven in part by advances in antibody engineering and the emergence of antibody-derived modalities. Among these, bispecific antibodies (bsAbs) and agonists have independently reshaped the therapeutic landscape by enabling novel mechanisms of action. However, the clinical development of agonists has been hampered by challenges such as systemic toxicity arising from excessive receptor activation and limited efficacy associated with inadequate receptor clustering or context-dependent signaling. To address these limitations, a distinct class of engineered molecules—agonistic bsAbs—has recently emerged as a promising therapeutic strategy. By spatially and contextually restricting receptor activation, these antibodies aim to enhance agonistic potency while improving safety and therapeutic index. Notably, in addition to their roles in cancer therapy, agonistic bsAbs also exhibit therapeutic potential in metabolic diseases. In this review, we classify agonistic bsAbs according to the nature of the receptors requiring activation, including immune co-stimulatory receptors, death receptors, and growth factor receptors. For each category, we summarize representative agonistic bsAbs, with a focus on their molecular design principles, mechanisms of action, preclinical and clinical progress, and current limitations. Together, this overview highlights agonistic bispecific antibodies as an evolving and versatile platform with the potential to redefine antibody-based therapeutics.