Recent advances of bispecific antibodies in solid tumors

Abstract

Cancer immunotherapy is the most exciting advancement in cancer therapy. Similar to immune checkpoint blockade and chimeric antigen receptor T cell (CAR-T), bispecific antibody (BsAb) is attracting more and more attention as a novel strategy of antitumor immunotherapy. BsAb not only offers an effective linkage between therapeutics (e.g., immune effector cells, radionuclides) and targets (e.g., tumor cells) but also simultaneously blocks two different oncogenic mediators. In recent decades, a variety of BsAb formats have been generated. According to the structure of Fc domain, BsAb can be classified into two types: IgG-like format and Fc-free format. Among these formats, bispecific T cell engagers (BiTEs) and triomabs are commonly investigated. BsAb has achieved an exciting breakthrough in hematological malignancies and promising outcome in solid tumor as showed in various clinical trials. In this review, we focus on the preclinical experiments and clinical studies of epithelial cell adhesion molecule (EpCAM), human epidermal growth factor receptor (HER) family, carcinoembryonic antigen (CEA), and prostate-specific membrane antigen (PSMA) related BsAbs in solid tumors, as well as discuss the challenges and corresponding approaches in clinical application.

Keywords: BsAb; CEA; EpCAM; HER family; PSMA; Radioimmunotherapy; Solid tumor.

Fig. 1

Molecular formats of bispecific antibodies. According to the Fc domain, BsAbs can be divided into two types: IgG-format molecules and non-IgG-format molecules. IgG-like BsAbs mainly include quandroma, knobs-into-holes, scFv-IgG, (IgG)2, scFv-Fc, and nanobody. The Fc-free BsAbs contain tandscFv, DART, TandAb, F(ab’)2, diabody, ImmTAC, Dock and Lock, and scFv-HSA-scF

Fig. 2

The comparison of BiTEs (taking MT110 as an example) and triomabs (taking catumaxomab as an example) killing mechanism. The interaction of T cells and tumor cells, which is mediated by BsAbs, initiates the killing process of T cells, including CD3 activation, formation of immunologic synapses, T-cell activation and proliferation, secretion of cytokines and cytotoxic granules, and tumor cell lysis [19]. The activated CD8⁺ and CD4⁺ T cells lyse cancer cells predominantly through perforin and granzyme B. The activated T cells secrete various cytokines such as IFN-γ, TNF, IL-2, IL-6, and IL-10 [20]. In addition to the above mechanism, triomabs can recruit other immune cells such as NK cells, macrophages which could kill tumor cells and mediate the co-stimulation between T cells and accessory cells [16]. Simultaneously recruiting and activating different immune effector cells to the tumor site result in potent tumor-cell elimination by the above different immunologic killing mechanisms

Fig. 3

The classical two-step protocol of pre-targeted radioimmunotherapy (taking TF2 as an example). The first step is to administer the TF2 to blood and offer adequate time for tumor uptake and clearance of excess TF2 in circulation. The second step is to infuse HSG. Finally, excess HSG is cleared from the bloodstream by kidneys