Applied Research Project

项目摘要-应用研究项目 我们的耗尽细胞的抗体资源在抗体的数量、质量和多样性方面都有了很大的增长。 过去的15年里。我们现在提议使用一种新的应用研究方法来提炼我们的资源，方法是 确定与治疗效果相关的基因型别。细胞耗竭治疗的成功已成定局 通过抗体与其配体结合并触发效应器机制的能力。当这些函数中的任何一个 是次理想的，患者可能出现部分或无衰竭。在人类中，对治疗的不同反应 细胞耗竭的单抗与Fcγ受体的特异性多态有关。 事实上，Fc受体(FCR)和抗体靶基因生物标记物目前被用来识别谁是 预计会对目标特工做出反应。虽然我们的大多数动物对细胞耗尽治疗有反应，但它是 通常的情况是，在一个给定的实验中，一两只动物(~10%)不会有有效的消耗水平。 因为缺乏治疗成功的机制尚未确定，研究人员也无法确定。 对研究动物进行预筛选，我们也无法设计出克服这一障碍的抗体。为了更好地利用我们的牢房- 因此，我们建议确定靶标和免疫效应器的遗传关联 基因与细胞耗竭治疗的成功。我们的初步数据表明，常见的 低效与有效细胞耗竭动物的FCR等位基因。我们将使用候选基因病例对照 有足够能力(n=220-250)来识别与以下各项相关的遗传标记的关联研究 治疗结果。识别预测有效耗竭的生物标记物将具有 通过允许研究人员在研究或治疗之前对动物进行筛查，对我们的资源产生直接影响 入会仪式。重要的是，这些信息可用于采取纠正措施和改善治疗效果， 要么排除反应不佳的人，要么修改治疗方案。在下一次细胞耗尽的过程中 在计划周期内，基因变异数据也将用于指导广泛功能抗体的设计 对抗常见的目标变种。最后，从长远来看，这些信息将被用来设计新一代 对常见表达的FCR具有高亲和力的恒河猴抗体。总而言之，我们建议确定 通过对编码我们的抗体或Fc受体的靶配体的基因进行测序来实现相关的多态 具有不同细胞耗竭结果的动物。这将通过1)生成生物标记物来改善我们的资源 与细胞去除疗法的疗效有关；2)指导开发最能识别的抗体 共同的目标变异；从长远来看，3)导致新一代恒河猴的发展 通过共同表达的FCR具有更好识别能力的抗体。

Project Summary – Applied Research Project Our cell-depleting antibody resource has expanded greatly in antibody quantity, quality, and diversity over the past 15 years. We are now proposing to use a new applied research approach to refine our resource, by identifying genotypes associated with therapy effectiveness. Success in cell-depletion treatments is determined by the antibody’s ability to engage with its ligand and trigger effector mechanisms. When either of these functions is suboptimal the patient might present a partial or no depletion. In humans, differential response to therapeutic cell-depleting monoclonal antibodies has been associated with specific polymorphisms in Fc gamma receptors. Indeed, Fc receptors (FcR) and antibody target gene biomarkers are currently used to identify patients who are predicted to respond to the targeted agents. While most of our animals respond to cell-depletion treatments, it is often the case that one or two animals (~10%) in a given experiment will not have efficient depletion levels. Because the mechanisms underlying the lack of therapy success are undetermined, neither can the investigators pre-screen study animals nor can we design antibodies that overcome this barrier. For best use of our cell- depleting resources, therefore, we are proposing to identify genetic associations of target and immune effector genes with cell-depletion treatment success. Our preliminary data suggest a differential distribution of common FcR alleles in animals with inefficient vs efficient cell depletion. We will use a candidate gene case-control association study that is sufficiently powered (n= 220-250) to identify genetic markers that correlate with treatment outcomes. The identification of biomarkers that are predictive of efficacious depletion would have an immediate impact on our resource, by allowing researchers to screen animals prior to study or treatment initiation. Importantly, this information can be used to take corrective actions and improve treatment performance, by either excluding poor responders or modifying therapy regimens. During the course of the next cell-depleting program cycle, the genetic variant data will also be used to guide the design of broadly functional antibodies against common target variants. Finally, in the long term, this information will be used to design a new generation of rhesus antibodies with high affinity to commonly expressed FcRs. In summary, are proposing to identify relevant polymorphisms by sequencing genes encoding the target ligands of our antibodies or Fc receptors from animals with divergent cell depletion outcomes. This will improve our resource by 1) generating biomarkers associated with cell depleting therapy efficacy; 2) guiding the development of antibodies that will recognize most common target variants; and, in the long term, 3) lead to the development of a new generation of rhesus antibodies with a superior recognition by commonly expressed FcRs.