Nonhuman primates (NHPs) continue to serve as 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 small animal models. Over the past decade, the number of NIH-funded research projects employing NHPs has increased by 50%. However, in the absence of readily available transgenic or gene knock-out primates, the utility of the NHP models is often limited by the availability of reagents capable of in vivo modulation of specific immune functions. In the preceding funding periods, this grant established the NIH Nonhuman Primate Reagent Resource, a program for developing and distributing antibody-based reagents that deplete specific lymphocyte subpopulations or target specific immune functions in vivo. In the past three years, this program has developed methods for generating and producing rhesus recombinant monoclonal antibodies with reduced immunogenicity and improved pharmacokinetics. Over this period, we distributed nearly 200 grams of antibody reagents supporting 48 NIH grants or intramural programs representing 8 NIH institutes or centers, and 11 non-NIH-funded programs. Furthermore, the technologies developed through this grant are also being utilized by an NIAID reagent contract which further supports investigators who use NHP models. As the need for these unique reagents continues to grow, new methods in protein engineering and expression are also emerging that will allow us to develop engineered antibodies with more focused targeting of cell subpopulations, defined effector function, and to produce them using more efficient expression methods. To continue support of NHP models across multidisciplinary scientific programs we will: 1. Develop """"""""next generation"""""""", engineered antibodies for targeting and depleting the major lymphocyte subsets in NHP 2. Engineer antibody Fc regions to modulate effector function 3. Generate fully rhesus monoclonal antibodies and explore the diversity of rhesus IgG 4. Produce IgG expression vectors for baboon, African green monkey and marmoset to enable production of recombinant antibodies for use in these other NHP species 5. Continue to produce and distribute these reagents to investigators using NHP models

Public Health Relevance

(provided by applicant): This program will facilitate better utilization of nonhuman primate models by developing and distributing unique research reagents, and support biomedical research across a wide range of scientific disciplines.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
Resource-Related Research Projects (R24)
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Special Emphasis Panel (ZRR1-CM-6 (01))
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O'Neill, Raymond R
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Beth Israel Deaconess Medical Center
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Hotta, Kiyohiko; Oura, Tetsu; Dehnadi, Abbas et al. (2018) Long-term Nonhuman Primate Renal Allograft Survival Without Ongoing Immunosuppression in Recipients of Delayed Donor Bone Marrow Transplantation. Transplantation 102:e128-e136
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O'Neill, Natalie A; Zhang, Tianshu; Braileanu, Gheorghe et al. (2018) Pilot Study of Delayed ICOS/ICOS-L Blockade With ?CD40 to Modulate Pathogenic Alloimmunity in a Primate Cardiac Allograft Model. Transplant Direct 4:e344
Choi, Se Hyun; Yoon, Chang Ho; Lee, Hyun Ju et al. (2018) Long-term safety outcome of systemic immunosuppression in pig-to-nonhuman primate corneal xenotransplantation. Xenotransplantation 25:e12442
Shin, Jun-Seop; Kim, Jong-Min; Min, Byoung-Hoon et al. (2018) Pre-clinical results in pig-to-non-human primate islet xenotransplantation using anti-CD40 antibody (2C10R4)-based immunosuppression. Xenotransplantation 25:

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