Monoclonal Antibody Development Expands to Include Theranostics

Robert L. Ferris, MD

One of the most exciting and successful historical demonstrations of translational immunotherapy is the development of monoclonal antibodies. Since the early 1900s when Paul Ehrlich, MD, envisioned these agents as “magic bullets,” monoclonal antibodies have been studied, coming into their own because of investigators’ ability to isolate and produce them in large-scale batches for research and clinical applications.

Large-scale batches for research and clinical applications. In 1984, Niels K. Jerne, MD; Georges J.F. Köhler, PhD; and César Milstein, PhD, who had discovered the principle for production of monoclonal antibodies, were awarded the 1984 Nobel Prize in Physiology or Medicine. Monoclonal antibodies demonstrated their potency and exquisite specificity for a particular target. An example is the linkage of chemotherapy as a payload onto the anti–HER2-specific antibody trastuzumab (Herceptin). In 2013, the FDA approved trastuzumab emtansine (T-DM1; Kadcyla) for HER2-expressing breast cancers resistant to trastuzumab or taxane chemotherapy.

Subsequently, the discovery that monoclonal antibodies could block inhibitory immune checkpoint receptors, such as PD-1 and CTLA-4, led to the 2018 Nobel Prize in Physiology or Medicine being awarded to James P. Allison, PhD, and Tasuku Honjo, MD, PhD.

The most recent development involves the field of theranostics, which uses radiolabeled monoclonal antibodies to target a particular tumor selective protein. In this issue of Targeted Therapies in Oncology, we review a series of theranostic strategies for not only diagnostic imaging of disseminated disease using radiolabeled monoclonal antibodies, but also for modifying the dosage and radioisotope to deliver therapeutic antitumor doses of the radiation in a highly targeted fashion, even for systemically metastatic cancer (see pages 30-34). There are now several theranostic antibodies that target cancer, the most recent being prostatespecific membrane antigen for prostate cancer.

The next generation of monoclonal antibodies can increase their targets in a single molecule, which are bispecific and trispecific, harnessing multiple specificities. These multimeric antibodies effectively increase the local concentration of antibody in the tumor microenvironment and harness the biology of multiple pathways that can be targeted for inhibition or stimulation, leading to more effective cancer therapy. These are truly amazing times that couple deep knowledge of biology with protein engineering, embodying the “magic bullets” envisioned more than 100 years ago.