UCSF

Cancer immunotherapies, or treatments that utilize a patient’s own immune system to fight cancer, have been met with a great deal of success. Although most current immunotherapies have focused on boosting the adaptive immune system, there has been a growing interest in targeting components of the innate immune system. An important member of the innate immune system is the natural killer (NK) cell. Like T cells, NK cells are cytotoxic effector cells with the ability to distinguish and eliminate virally infected or transformed cells. They play a key role in the anti-tumor response and are able to identify target cells by recognizing stress-induced ligands that are frequently overexpressed on cancer cells. NK cells are best known for their ability to perform antibody-dependent cellular cytotoxicity (ADCC), a mechanism that is used by several therapeutic antibodies to eradicate tumor cells. Whereas all T cells can be targeted through the T cell receptor (TCR)/CD3 complex, NK cells have multiple activating, costimulatory, and inhibitory receptors that can be targeted to modulate their activity. This dissertation provides a strategy used to identify antibodies that can target and stimulate NK cells and the development of bispecific antibodies to redirect NK cell-mediated cytotoxicity towards tumor cells of interest. Chapter 1 discusses the background of NK cells and their role in anti-tumor immunity. Chapter 2 describes a mass spectrometry-based screening approach to identify cell surface proteins on NK cells. Chapter 3 provides the method designed to identify antibodies that are able to stimulate NK cell-mediated cytotoxicity and the generation of bispecific NK engagers.