Research and clinical landscape of bispecific antibodies for the treatment of solid malignancies

Solid tumors adopt multiple mechanisms to grow, evade immune responses, and to withstand therapeutic approaches. A major breakthrough in the armamentarium of anti-cancer agents has been the introduction of monoclonal antibodies (mAbs), able to inhibit aberrantly activated pathways and/or to unleash antigen (Ag)-specific immune responses. Nonetheless, mAb-mediated targeted pressure often fails due to escape mechanisms, mainly Ag loss/downregulation, ultimately providing therapy resistance. Hence, in order to target multiple Ag at the same time, and to facilitate cancer-immune cells interactions, bispecific antibodies (bsAbs) have been developed and are being tested in clinical trials, yielding variable safety/efficacy results based on target selection and their structure. While in hematologic cancers the bsAb blinatumomab recently reached the Food and Drug Administration (FDA)-approval for B Cell Acute Lymphoblastic Leukemia, bsAbs use in solid tumors faces considerable challenges, such as target Ag selection, biodistribution, and the presence of an immune-suppressive tumor microenvironment (TME). This review will focus on the state-of-the art, the design, and the exploitation of bsAbs against solid malignancies, delineating their mechanisms of action, major pitfalls, and future directions.