Bispecific antibodies in cancer immunotherapy

Abstract

Following the clinical success of immune checkpoint antibodies targeting CTLA-4, PD-1 or PD-L1 in cancer treatment, bispecific antibodies are now emerging as a growing class of immunotherapies with potential to further improve clinical efficacy and safety. We describe three classes of immunotherapeutic bispecific antibodies: (a) cytotoxic effector cell redirectors; (b) tumor-targeted immunomodulators; and (c) dual immunomodulators. Cytotoxic effector cell redirectors are dominated by T-cell redirecting compounds, bispecific compounds engaging a tumor-associated antigen and the T-cell receptor/CD3 complex, thereby redirecting T-cell cytotoxicity to malignant cells. This is the most established class of bispecific immunotherapies, with two compounds having reached the market and numerous compounds in clinical development. Tumor-targeted immunomodulators are bispecific compounds binding to a tumor-associated antigen and an immunomodulating receptor, such as CD40 or 4-1BB. Such compounds are usually designed to be inactive until binding the tumor antigen, thereby localizing immune stimulation to the tumor environment, while minimizing immune activation elsewhere. This is expected to induce powerful activation of tumor-specific T cells with reduced risk of immune-related adverse events. Finally, dual immunomodulators are bispecific compounds that bind two distinct immunomodulating targets, often combining targeting of PD-1 or PD-L1 with that of LAG-3 or TIM-3. The rationale is to induce superior tumor immunity compared to monospecific antibodies to the same targets. In this review, we describe each of these classes of bispecific antibodies, and present examples of compounds in development.

Keywords: bispecific antibody; cancer; checkpoint; co-stimulation; immuno-oncology; immunotherapy.

Figure 1.

T-cell redirection. T-cell redirecting therapies are bispecific compounds targeting a tumor antigen expressed by the malignant cell, and CD3 expressed by the T-cell. Upon binding to both targets, the compound redirects T-cell cytotoxicity toward the malignant cells. This effect is independent of T-cell specificity, and is mainly mediated by non-tumor-specific T cells.

Figure 2.

Tumor-targeted immunomodulators. Tumor-targeted immunomodulators are bispecific compounds targeting a tumor antigen expressed by the malignant cell, and an immunomodulatory receptor expressed by tumor-infiltrating immune cells. By activation of the immunomodulatory receptor, the preexisting, tumor-specific immune response induced in the tumor environment by the interplay between antigen-presenting cells, T cells and tumor cells is stimulated. Tumor-targeted immunomodulators may either activate antigen-presenting cells, for example via the CD40 pathway, stimulating their ability to induce a potent antitumor immune response (a); or they may act directly on tumor-specific T cells, for example by activation of 4-1BB (b).

Figure 3.

Dual immunomodulators. Dual immunomodulators are bispecific compounds binding two distinct immunomodulating targets. Most such compounds block two inhibitory checkpoint pathways, thereby reducing the immunosuppressive mechanisms inhibiting tumor immunity.