Clinical Progresses and Challenges of Bispecific Antibodies for the Treatment of Solid Tumors

Abstract

In recent years, bispecific antibodies (BsAbs) have emerged as a promising therapeutic strategy against tumors. BsAbs can recruit and activate immune cells, block multiple signaling pathways, and deliver therapeutic payloads directly to tumor sites. This review provides a comprehensive overview of the recent advances in the development and clinical application of BsAbs for the treatment of solid tumors. We discuss the different formats, the unique mechanisms of action, and the clinical outcomes of the most advanced BsAbs in solid tumor therapy. Several studies have also analyzed the clinical progress of bispecific antibodies. However, this review distinguishes itself by exploring the challenges associated with bispecific antibodies and proposing potential solutions. As the field progresses, BsAbs hold promise to redefine cancer treatment paradigms and offer new hope to patients with solid tumors.

Fig. 1

Several representative formats of bispecific antibodies (BsAbs). The formats of BsAbs are categorized according to the presence or absence of the Fc region. IgG Immunoglobulin G, scFv single-chain variable fragment, VH the variable region of a heavy chain, VL the variable region of a light chain, BiTE bispecific t-cell engagers, DART dual affinity re-targeting proteins, TandAb tandem diabodies, Fab fragment antigen-binding, Fc fragment crystallizable, DVD-Ig the dual variable domain immunoglobulin, KiH knobs-into-holes, Common LC common light chain

Fig. 2

Mechanisms of bispecific antibodies (BsAbs) in tumor therapy. a BsAbs engage immune cells (such as T cells or NK cells) with tumor cells by binding to CD3 or CD16 on immune cells and targeting tumor-associated antigens (TAAs) on tumor cells, mediating the release of cytokines by immune cells and triggers antibody-dependent cellular cytotoxicity (ADCC). b An example of TAAs targeting BsAbs: a BsAb targets HER2 and HER3, blocking the downstream signaling pathway. c BsAbs inhibit immune checkpoints like PD-L1 on cancer cells or PD-L1 and CTLA-4 on T cells, blocking inhibitory signals that prevent T cells from attacking tumor cells, thereby modulating the immune responses. d BsAbs can serve as precision delivery vehicles for therapeutic payloads, directly conveying drugs to tumor cells and thus aiding in their treatment