Development of Antibody Tools to Interrogate and Modulate Cellular Signaling in Cancer

Over the last two decades, a major focus in the biomedical research community has been placed on understanding the interaction between the human immune system and cancer. This focus has led to a considerably improved understanding of how cancer can evade immune detection, and as a consequence, the emergence of a novel class of cancer therapeutics that can trigger the immune system to recognize and eliminate previously undetected cancers. These new therapies, known as cancer immunotherapies, have resulted in unprecedented and remarkably durable outcomes in the clinic. However, there are key limitations that continue to hinder how broadly immunotherapies can be applied to treat human cancers. The research in this thesis describes efforts to apply antibody engineering as a tool to address some of these limitations.Antibodies that recognize tumor specific antigens can serve as guides to target the immune system directly to cancer cells. However, for many cancer types, there are currently no known tumor specific antigens. This paucity of available targets continues to present a major challenge in the immunotherapy field. Chapter 1 describes the development of a technological pipeline that coupled proteomics to antibody discovery in order to discover and begin to validate novel tumor specific antigens on the cell surface proteome of Ras driven cancers. Ras driven cancers represent nearly a third of all human malignancies. The work in this chapter presents a new series of molecular targets that could potentially be leveraged to target the immune system to this large class of difficult to target cancers.Another major challenge in the immunotherapy space is that the treatments often work too well. The result is rapid hyperactivation of the immune system, often leading to horrible side effects faced by patients including severe fevers, neurotoxicity, and sometimes death. A prevailing thought in the community is that a more gradual activation of this immune response might ameliorate side effects while maintaining efficacy. Chapter 2 describes the development of a new class of molecular switches called Antibody-based Chemically Inducible Dimerizers that enable immune cell activation to be precisely regulated by administration of small molecule drugs