The enhanced antitumor activity of bispecific antibody targeting PD-1/PD-L1 signaling

Abstract

The programmed cell death 1 (PD-1) signaling pathway, a key player in immune checkpoint regulation, has become a focal point in cancer immunotherapy. In the context of cancer, upregulated PD-L1 on tumor cells can result in T cell exhaustion and immune evasion, fostering tumor progression. The advent of PD-1/PD-L1 inhibitor has demonstrated clinical success by unleashing T cells from exhaustion. Nevertheless, challenges such as resistance and adverse effects have spurred the exploration of innovative strategies, with bispecific antibodies (BsAbs) emerging as a promising frontier. BsAbs offer a multifaceted approach to cancer immunotherapy by simultaneously targeting PD-L1 and other immune regulatory molecules. We focus on recent advancements in PD-1/PD-L1 therapy with a particular emphasis on the development and potential of BsAbs, especially in the context of solid tumors. Various BsAb products targeting PD-1 signaling are discussed, highlighting their unique mechanisms of action and therapeutic potential. Noteworthy examples include anti-TGFβ × PD-L1, anti-CD47 × PD-L1, anti-VEGF × PD-L1, anti-4-1BB × PD-L1, anti-LAG-3 × PD-L1, and anti-PD-1 × CTLA-4 BsAbs. Besides, we summarize ongoing clinical studies evaluating the efficacy and safety of these innovative BsAb agents. By unraveling the intricacies of the tumor microenvironment and harnessing the synergistic effects of anti-PD-1/PD-L1 BsAbs, there exists the potential to elevate the precision and efficacy of cancer immunotherapy, ultimately enabling the development of personalized treatment strategies tailored to individual patient profiles.

Keywords: 4-1BB; Bispecific antibody; CD47; Cancer immunotherapy; PD-1; PD-L1; TGFβ; VEGF.

Fig. 1

Bispecific antibodies (BsAbs) enhance tumor killing by guiding various effector cells to tumor cells in a non-MHC-restricted manner. BsAbs facilitate the interaction between T cells and tumor cells, triggering a sequence of events leading to T cell activation. The primary mechanism employed by activated T cells in cancer cell lysis involves Granzyme-B and perforin (Adapted from “Bispecific Antibody Mechanism of Action”, by BioRender 2023)

Fig. 2

The tumor-killing mechanisms of blinatumomab and TrioMabs. Blinatumomab is an anti-CD3 × CD19 bispecific T-cell engager (BiTE) antibody. Blinatumomab is designed to bind to both CD19 of B cells and CD3 of T cells. By linking these two cell types, blinatumomab helps facilitate the T cell response against cancer cells, leading to the destruction of B-cell leukemia cells. Catumaxomab is an anti-CD3 × EpCAM BsAb based on TrioMabs technique, binding to EpCAM of cancer cells and CD3 of T cells. Notably, the Fc domain could bind to Fcγ receptor of effector cells including NK cells, macrophages, and dendritic cells, triggering antibody-dependent cell cytotoxicity or phagocytosis, and complement-dependent cytotoxicity against cancer cells (Adapted from “Bispecific Antibody Design”, by BioRender 2023)

Fig. 3

BsAbs simultaneously targeting two immunoinhibitory molecules on tumor cells or cytokines in the TME. In contrast to BiTEs, these bispecific antibodies aim to block two immunoinhibitory signaling pathways (except 4-1BB agonist antibodies), generating synergistic anti-cancer effects or minimizing drug resistance (Created with Biorender)