Bispecific monoclonal antibodies for targeted immunotherapy of solid tumors: Recent advances and clinical trials

Bispecific antibodie (BsAbs) combine two or more epitope-recognizing sequences into a single protein molecule. The first therapeutic applications of BsAbs were focused on cancer therapy. However, these antibodies have grown to cover a wider disease spectrum, including imaging, diagnosis, prophylaxis, and therapy of inflammatory and autoimmune diseases. BsAbs can be categorized into IgG-like formats and non-IgG-like formats. Different technologies have been used for the construction of BsAbs including "CrossMAb", "Quadroma", "knobs-into-holes" and molecular cloning. The mechanism of action for BsAbs includes the induction of CDC, ADCC, ADCP, apoptosis, and recruitment of cell surface receptors, as well as activation or inhibition of signaling pathways. The first clinical trials included mainly leukemia and lymphoma, but solid tumors are now being investigated. The BsAbs bind to a tumor-specific antigen using one epitope, while the second epitope binds to immune cell receptors such as CD3, CD16, CD64, and CD89, with the goal of stimulating the immune response against cancer cells. Currently, over 20 different commercial methods have been developed for the construction of BsAbs. Three BsAbs are currently clinically approved and marketed, and more than 85 clinical trials are in progress. In the present review, we discuss recent trends in the design, engineering, clinical applications, and clinical trials of BsAbs in solid tumors.