Bispecific Antibodies in Solid Tumors: Advances and Challenges

Abstract

Bispecific antibodies (BsAbs) have shown potential in cancer treatment and have become a rapidly growing field in cancer immunotherapy. Unlike monoclonal antibodies with two identical binding sites, BsAbs simultaneously bind two distinct epitopes on the same or different antigens, allowing for a range of mechanisms of action, including engaging immune cells to kill cancer cells and blocking signaling pathways. Despite regulatory approvals for hematological malignancies in the last decade, their clinical success in solid malignancies has been lacking until recently. There are currently five BsAbs approved by the FDA in the United States for solid tumors-amivantamab, tarlatamab, tebentafusp, zanidatamab and zenocutuzumab-and two BsAbs approved in China-cadonilimab and ivonescimab. Currently, several BsAbs are under clinical development for solid tumors, but are mostly in early phase I and II trials. This review provides an overview of the basic mechanism of action of BsAbs, current FDA-approved BsAbs, and current BsAbs under clinical development, their challenges in clinical use, the management of toxicities, and future directions.

Keywords: bispecific T cell engager; bispecific antibodies; cytokine release syndrome; personalized cancer therapy; precision medicine; targeted therapy.

Figure 1

Mechanism of action of BsAbs: (1) Immune cell engagement—BsAbs can crosslink to either CD3 on T cells or CD16 on NK cells and TAA on tumor cells, which can lead to the activation of T or NK cells, causing the release of cytokines, perforins and granzyme B and lysis of tumor cells. (2) Immune checkpoint modulation—BsAbs can simultaneously bind to PD-L1 on tumor cells (or antigen-presenting cells) and either PD-1, CTLA-4, or LAG-3 on T cells, activating T cell response and the release of perforins and granzyme B and lysis of tumor cells. (3) Tumor-associated antigen blockade—BsAbs can simultaneously bind different targets TAA1 and TAA2 (such as EGFR and cMET receptors) on tumor cells and block phosphorylation and downstream signaling pathways or it can bind simultaneously to different domains on the same target TAA1a and TAA1b (such as two distinct domains of HER2 receptor), thus preventing dimerization and downstream signaling pathways.

Figure 2

Resistance to BsAbs due to loss of antigen expression via internalization (endocytosis), proteolytic shedding of the target, genetic mutations in genes encoding the target antigen, epigenetic regulation (silencing of gene expression via DNA methylation or histone modification leading to transcriptional downregulation), alternative splicing (splice variants that do not present epitopes recognized by BsAbs), or clonal selection (tumor cells lacking the target antigen of BsAb therapy can survive and expand, leading to a resistant population).