When three is not a crowd: trispecific antibodies for enhanced cancer immunotherapy

Abstract

Despite the clinical success of the first bispecific antibody approved by the FDA against B cell malignancies (blinatumomab), many obstacles remain such as dosing, treatment resistance, and modest efficacy in solid tumors. To overcome these limitations, considerable efforts have been dedicated to the development of multispecific antibodies, opening up new avenues to address both the complex biology of cancer and the onset of anti-tumoral immune responses. Simultaneous targeting of two tumor-associated antigens is presumed to enhance cancer cell selectivity and reduce immune escape. Co-engagement of CD3, along with agonists of co-stimulatory molecules or antagonists of co-inhibitory immune checkpoint receptors in a single molecule, may revert T cell exhaustion. Similarly, targeting of two activating receptors in NK cells may improve their cytotoxic potency. And these are only examples of the potential of antibody-based molecular entities engaging three (or more) relevant targets. From the perspective of health care costs, multispecific antibodies are appealing, since a similar (or superior) therapeutic effect could be obtained with a single therapeutic agent as with a combination of different monoclonal antibodies. Despite challenges in production, multispecific antibodies are endowed with unprecedented properties, which may render them more potent biologics for cancer therapy.

Metabolic adaptations determine whether natural killer cells fail or thrive within the tumor microenvironment

“…221 The use of TriKEs has been tested in multiple preclinical studies against AML and various solid tumors including ovarian cancer. 222 Targeted administration of cytokines in the tumor is required to ensure that these cytokines exert their effects within the TME to limit effects on healthy cells. One way to achieve this is through OVs as they can be engineered to express pro-inflammatory factors and replicate within tumor cells.…”

The Evolving Landscape of Antibody–Drug Conjugates: In Depth Analysis of Recent Research Progress

“…Trispecific antibodies are designed to bind to three different targets or antigens. They offer even greater targeting specificity, potentially allowing for more precise delivery of cytotoxic payloads to tumor cells while sparing healthy tissues …”

“…They offer even greater targeting specificity, potentially allowing for more precise delivery of cytotoxic payloads to tumor cells while sparing healthy tissues. 542 By integration of these advanced antibody formats into ADCs, it becomes possible to achieve several goals simultaneously: enhanced target specificity, improved tissue penetration, engagement of the immune system, and reduction in systemic toxicity. These advanced ADC strategies hold great promise for improving the efficacy and safety of cancer therapies and other targeted treatments.…”

Trispecific antibodies for cancer immunotherapy

“…Till date, no TsAb has been approved for clinical use. However, a wide range of drugs are in preclinical and clinical development stage [67]. For example, FDA has granted Fast Track designation to HPN217, a BCMA‐targeting TsAb, for the treatment of patients with relapsed, refractory multiple myeloma.…”