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.

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

“…These dual antibodies can physically draw two key components in the immunologic synapse into close proximity, and boost the downstream immune response. There are several classifications of bispecifics, reviewed in, and including cytotoxic effector cell redirectors targeting T cells or NK cells, tumor‐targeted immunomodulators, or dual immunomodulators. Bispecific T‐cell engagers generally include an antibody to a tumor‐specific antigen, as well as an antibody targeting CD3 expressed by the T cells.…”

Retracted: Dual targeting of RANKL and PD‐1 with a bispecific antibody improves anti‐tumor immunity

“…18,19 In immuno-oncology, increased anti-tumor efficacy and avoidance of resistance may be achieved with BsAbs, compared with the combination of mAb approaches, because of a more complete antagonism of two immunomodulatory pathways simultaneously via avidity effects and a more selective activation of the immune system within the TME. 18,19 In immuno-oncology, increased anti-tumor efficacy and avoidance of resistance may be achieved with BsAbs, compared with the combination of mAb approaches, because of a more complete antagonism of two immunomodulatory pathways simultaneously via avidity effects and a more selective activation of the immune system within the TME.…”

“…Bispecific antibody (BsAb) as a modality to target two antigens simultaneously is an emerging strategy to improve clinical efficacy compared with the combination of two separate mAbs. 18,19 In immuno-oncology, increased anti-tumor efficacy and avoidance of resistance may be achieved with BsAbs, compared with the combination of mAb approaches, because of a more complete antagonism of two immunomodulatory pathways simultaneously via avidity effects and a more selective activation of the immune system within the TME. A more tumor-specific delivery of BsAb resulting from increased target expression within the TME may not only enhance tumor control but also reduce systemic toxicities.…”

An engineered 4-1BBL fusion protein with “activity-on-demand”

“…The approach described in this article should be generally applicable to members of the TNF superfamily. Alternative approaches may involve bispecific antibodies 93,94 , the modular use of small protein domains 85,95 or of chemically-modified bicyclic peptides 96 . Members of the TNF receptor superfamily are particularly suited for cooperative activation strategies in view of their homotrimeric structure and clustering-driven activation properties [97][98][99] .…”