With ADCs, Tumor-Targeted Antibodies Leap Forward

Robert L. Ferris, MD, PhD

Director

Hillman Cancer Center

University of Pittsburgh Medical Center

Pittsburgh, PA

We are witnessing an exciting advancement in cancer treatment by labeling tumor-targeted antibodies with various toxic modalities, including chemotherapy and radioisotopes. Using these cytotoxic payloads, we can deliver improved lytic chemotherapeutics and systemic radiotherapies. Th is new approach was predicated more than 20 years ago with the development of tumor-targeted antibodies themselves. Although tumor-targeted antibodies were initially employed for their inhibition of oncogenic signaling through a defined cell surface receptor, such as HER2 or EGFR, newer targets such as Trop2 have been developed with broad expression across cancer types.

In the setting of various payload chemotherapies, these may harness different toxic pathways intracellularly, such as microtubule disruption. Other payloads are actively being developed for the antibody-drug conjugate field, with several companies focused on enabling the combination of antibody portfolios with payload drug pipelines. In addition to tumor lysis, indirect benefits, such as microenvironment effects, may lead to enhanced immune recognition via types of tumor cell death or other salutatory benefits. Understanding the relative contribution of each of these mechanisms, including the original inhibitory effect of the antibody itself, is ongoing and could be additive between the different mechanisms.

Regarding the use of radioisotope payloads, the concept of theranostic treatments is exciting and rapidly developing. The different isotope characteristics may enhance cellular targeting and avoid toxicity, as well as deliver immunogenic radiation in a way that is immune friendly and lymphocyte sparing from the deleterious effects of external beam fractionated radiation. In all, the concept of repurposing existing antibodies and targets with various payloads indicates the ingenuity and protein-engineering potential of rapidly evolving cancer treatment.

Targeted antibodies is also expanding with bispecific antibodies targeting 2 receptors, and thus a targeting single tumor moiety may soon be considered old fashioned. Meanwhile, the discovery of appropriate new targets continues, with an eye toward avoiding broad expression on normal tissues. This will add layers of therapies harnessing 1 or more targets, which may need to be sequenced to avoid resistance and to prolong lives and quality of life.