Current landscape and future directions of bispecific antibodies in cancer immunotherapy

Abstract

Recent advances in cancer immunotherapy using monoclonal antibodies have dramatically revolutionized the therapeutic strategy against advanced malignancies, inspiring the exploration of various types of therapeutic antibodies. Bispecific antibodies (BsAbs) are recombinant molecules containing two different antigens or epitopes identifying binding domains. Bispecific antibody-based tumor immunotherapy has gained broad potential in preclinical and clinical investigations in a variety of tumor types following regulatory approval of newly developed technologies involving bispecific and multispecific antibodies. Meanwhile, a series of challenges such as antibody immunogenicity, tumor heterogeneity, low response rate, treatment resistance, and systemic adverse effects hinder the application of BsAbs. In this review, we provide insights into the various architecture of BsAbs, focus on BsAbs' alternative different mechanisms of action and clinical progression, and discuss relevant approaches to overcome existing challenges in BsAbs clinical application.

Keywords: bispecific T cell engager; bispecific antibodies; cancer immunotherapy; clinical trials; tumor microenvironment (TME).

Figure 1

CD3+ bispecific T-cell engaging antibodies exert function in Hematological Malignancies and recruit immune cells into the solid tumor microenvironment for cancer immunotherapy. The schematic depicts the mechanism of action of BsAbs in solid tumors (A) and Hematological Malignancies (B). besides, there shows partial fragments of antibody as well as the derivatives formats constructed from them in diagram (C) and various architecture of BsAbs in diagram (D) mentioned in this review.

Figure 2

Bispecific antibodies exert anti-tumor effects in the immunosuppressive tumor microenvironment. In the complex tumor microenvironment, activated fibroblasts communicate with tumor cells, various inflammatory cells as well as stroma cells via secreting growth factors (TGFβ, VEGF, etc.) and other chemokines to provide potentially oncogenic signals and interact with the microvasculature, which induces an accelerated oncogenic extracellular-matrix microenvironment. BsAbs, aiming at blocking the interacting mechanism, transform the “cold” immune environment into the “hot” immune environment.