Magnani_P40_Applied Research

Project Summary – Applied Research Component Nonhuman primate (NHP) studies have provided essential knowledge of fundamental mechanisms of disease pathogenesis and advanced biomedical research. Our work under the P40-funded Nonhuman Primate Antibody Resource for Immune Cell Depletion has substantially advanced NHP research by developing novel antibody reagents that are vital for performing these studies. An important step in generating these antibodies is “primatizing” them to reduce immunogenicity and improve their compatibility in the NHP model. “Primatizing” antibodies is not trivial, and our group at the Nonhuman Primate Reagent Resource (NHPRR) has led the field in developing this process over the past 24 years, applying multiple strategies, including grafting the complementarity-determining regions (CDRs), ‘resurfacing’ residues in contact with the antigen, and in silico structural modeling. These methods have allowed us to design and generate primatized antibodies that are critical to the NHP research community and have led to over 240 peer-reviewed publications. Despite these advances, the process of identifying and primatizing antibodies is a rate-limiting step in NHP research, and there are pitfalls in the process that still need to be addressed. For example, past strategies to primatize antibodies consisted of grafting another species variable region, which can lead to the production of antidrug antibodies, or grafting the CDR in an NHP antibody, which might decrease the antibody affinity. In the Applied Research Component, we will incorporate recent advances, such as innovative machine learning techniques and yeast surface display approaches, to increase our antibody screening capabilities by six orders of magnitude and create NHP antibodies with less immunogenicity and higher affinities. This innovative approach has the potential to substantially reduce the development time of NHP antibodies. We will apply this strategy to develop the first primatized antibodies to deplete Natural Killer (NK) cells—a major immune cell type. These reagents will be a significant resource for researchers across multiple fields of study, including virology, cancer biology, transplant biology, and autoimmune diseases. The goals of the Applied Research Component are to (1) enable the development of primatized antibodies with higher homology to native NHP molecules, (2) expand the availability of antibody clones that can be used in NHP studies, and (3) allow for the development of primatized antibodies with custom-binding properties (e.g., enhanced selectivity/specificity to antigens of NHP origin). The Applied Research Component will conduct one Ab primatization campaign per year, prioritized by the External Advisory Board. If successful, we will implement a new workflow for antibody optimization in this resource that will greatly facilitate the engineering of tailored antibodies for NHP studies. Ultimately, making NHP animal models more useful to the research community.