Nonhuman primates (NHPs) provide powerful animal models for exploring the pathogenesis of infectious and noninfectious diseases, and for testing of new therapies and vaccines that cannot be evaluated in rodents. Over the past decade, the number of NIH grants employing nonhuman primates has doubled. However, the utility of these models in many cases is limited by the availability of reagents for in vitro diagnostics and for in vivo modulation of specific immune functions. During the previous funding period of this grant, we established the NIH Nonhuman Primate Reagent Resource, a program for identifying and/or developing monoclonal antibodies, including new mouse-human chimeric recombinant monoclonal antibodies, fully-human monoclonal antibodies and rhesus receptor/human Ig fusion proteins that deplete specific lymphocyte subpopulations or target specific immune functions in vivo. We also established processes for large-scale production of reagents and optimized their use. During this initial award period, we distributed 90,000 milligrams of purified monoclonal antibody supporting more than 60 NIH grants or intramural programs representing 8 NIH institutes or centers. The need for these unique reagents has grown steadily since the initiation of this program. In addition, the potential has emerged to develop new reagents with reduced antigenicity, longer duration of effect in vivo and more focused targeting of lymphocyte subpopulations. To continue support of nonhuman primate models across multidisciplinary scientific programs we will: 1) Produce and distribute recombinant antibodies and fusion proteins developed during the previous funding period, 2) Identify and/or develop reagents, including recombinant (chimeric, humanized and primatized) mAbs, with new specificities and functions as directed by a scientific advisory committee, 3) Develop macaque IgG vectors for generating recombinant rhesus antibodies and rhesus Ig-Fc fusion proteins, and assess the in vivo biological properties of recombinant rhesus lgG1, lgG2 and lgG4 antibodies, 4) Explore methods of increasing recombinant antibody plasma half-life by increasing affinity for FcRn, and 5) Determine if experimental lymphocyte depletion reactivates viruses that are endemic in captive NHPs potentially affecting experimental outcome or having public health considerations.
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