Recent advances and challenges of bispecific antibodies in solid tumors

Abstract

Cancer immunotherapy has made remarkable progress in the past decade. Bispecific antibodies (BsAbs) have acquired much attention as the next generation strategy of antibody-target cancer immunotherapy, which overwhelmingly focus on T cell recruitment and dual receptors blockade. So far, BsAb drugs have been proved clinically effective and approved for the treatment of hematologic malignancies, but no BsAb have been approved in solid tumors. Numerous designed BsAb drugs for solid tumors are now undergoing evaluation in clinical trials. In this review, we will introduce the formats of bispecific antibodies, and then update the latest preclinical studies and clinical trials in solid tumors of BsAbs targeting EpCAM, CEA, PMSA, ErbB family, and so on. Finally, we discuss the BsAb-related adverse effects and the alternative strategy for future study.

Keywords: BsAb; CEA; EGFR; EpCAM; HER2; PSMA; Solid tumor.

Fig. 1

Structure of nature IgG antibody and different formats of bispecific antibodies according to the presence and absence of an Fc region. a Structure of nature IgG molecule. b fragment-based BsAbs contain Diabody, DART, Tandem diabodies, F(ab)2, Dock and Lock. c IgG-like BsAbs mainly include DVD-Ig, Quadromas, mAb2, scFv-Fab IgG, CrossMab, IgG-(scFc)2 and (scFv)4-Fc

Fig. 2

The killing mechanism of TrioMabs (taking Catumaxomab as an example). TrioMabs is a trifunctional BsAb with one arm targeting TAA on tumor cells, another arm targeting CD3 on T cells and the Fc domain binding to Fcγ receptor type I, IIa and III on effector cells such as macrophages, dendritic cells, and NK cells. Once the Fc region of BsAb binds to Fcγ receptor expressed by effector cells or complement component 1q (C1q), these effector cells are activated and release perforins and granzymes from its granules, potentially supporting the destruction of target cells through ADCC, ADCP and CDC, respectively [24]. Additionally, T cells are activated, accompanied by the release of T cell cytokines such as TNF-α and IFN-γ with high levels of proinflammatory cytokines such as IL-6, IL-12, GM-CSF, and DC-CK1 [34, 35]