Resource for Nonhuman Primate Cell Depleting Antibodies

描述(申请人提供)：非人灵长类动物(NHP)继续作为强大的动物模型，用于探索传染病和非传染性疾病的发病机制，并测试无法在小动物模型中评估的新疗法和疫苗。在过去的十年里，NIH资助的使用NHP的研究项目的数量增加了50%。然而，在缺乏现成的转基因或基因敲除灵长类动物的情况下，NHP模型的实用性往往受到能够在体内调节特定免疫功能的试剂的可用性的限制。在之前的资助期间，这笔赠款建立了NIH非人灵长类试剂资源，这是一个开发和分发基于抗体的试剂的计划，这些试剂耗尽体内特定的淋巴细胞亚群或靶向特定的免疫功能。在过去的三年里，该计划开发了产生和生产猕猴重组单抗的方法，这些抗体降低了免疫原性，改善了药代动力学。在此期间，我们分发了近200克抗体试剂，支持代表8个NIH研究所或中心的48个NIH赠款或校内项目，以及11个非NIH资助的项目。此外，通过这笔赠款开发的技术也被NIAID试剂合同所利用，该合同进一步支持使用NHP模型的研究人员。随着对这些独特试剂的需求持续增长，蛋白质工程和表达方面的新方法也在不断涌现，这将使我们能够开发出针对细胞亚群的、明确的效应功能的工程抗体，并使用更有效的表达方法来生产它们。为了在多学科科学项目中继续支持NHP模型，我们将：1.开发针对和耗尽NHP中主要淋巴细胞亚群的下一代工程抗体2.设计抗体Fc区以调节效应器功能3.产生完整的恒河猴单抗并探索恒河猴Ig G的多样性4.生产恒河猴、非洲绿猴和绒猴的Ig G表达载体，以生产用于这些其他NHP物种的重组抗体5.继续生产这些试剂，并使用NHP模型将这些试剂分发给研究人员 公共卫生相关性(由申请者提供)：该计划将通过开发和分发独特的研究试剂，促进更好地利用非人类灵长类动物模型，并支持广泛科学学科的生物医学研究。

DESCRIPTION (provided by applicant): 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.