CD47 is a cell-surface molecule that acts as a "don't eat me" signal to the host immune system. By signaling through SIRP?, an inhibitory receptor found on the surface of macrophages, CD47 is able to inhibit phagocytosis. Many cancer cells upregulate CD47 expression on their surface, allowing them to avoid ingestion by macrophages. However, antibodies that block the interaction between CD47 and SIRP? increase phagocytosis and eliminate tumors in a number of pre-clinical models. A similar blocking reagent could be developed by producing a soluble form of SIRP?. The use of such a molecule could be more efficacious as it would bind the entire interface of CD47 to block signaling. However, the weak interaction between native SIRP? and CD47 limits the efficacy of such a therapy. For this reason, a yeast-display system was used to bioengineer SIRP? mutants with increased binding affinity for human CD47. The goal of this proposal is to characterize the biochemical properties of these SIRP? mutant proteins and evaluate their efficacy as immunostimulatory cancer therapeutics. First, the biochemical properties of the SIRP? mutants will be measured by surface plasmon resonance (Aim 1). Next, the functional efficacy of the SIRP? mutants will be tested in vitro using purified macrophages and human cancer cells (Aim 2). Last, in vivo efficacy of the SIRP? mutant proteins will be evaluated using pre-clinical xenotransplantation mouse models of human tumors (Aim 3). Since CD47 is a common mechanism that tumor cells use to evade the immune system, the molecules evaluated in this study could be effective immune-based therapies for many types of cancer.
Macrophages are immune cells found in human tissues that ingest debris, bacteria, and other pathogens. The goal of this proposal is to develop novel therapies that stimulate macrophages to attack tumor cells as a way of eliminating multiple types of human cancer.
|Kohrt, Holbrook E; Colevas, A Dimitrios; Houot, Roch et al. (2014) Targeting CD137 enhances the efficacy of cetuximab. J Clin Invest 124:2668-82|
|Tseng, Diane; Volkmer, Jens-Peter; Willingham, Stephen B et al. (2013) Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc Natl Acad Sci U S A 110:11103-8|
|Weiskopf, Kipp; Ring, Aaron M; Ho, Chia Chi M et al. (2013) Engineered SIRP* variants as immunotherapeutic adjuvants to anticancer antibodies. Science 341:88-91|
|Edris, Badreddin; Willingham, Stephen B; Weiskopf, Kipp et al. (2013) Anti-KIT monoclonal antibody inhibits imatinib-resistant gastrointestinal stromal tumor growth. Proc Natl Acad Sci U S A 110:3501-6|