Applied Research Project

应用研究项目

• 批准号: 10540241
• 负责人: Kathleen Engelman
• 金额: $ 5.56万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10540241
• 关键词: Affect; Affinity; Alleles; Animals; Antibodies; Antibody Affinity; Applied Research; Biological Markers; Candidate Disease Gene; Cells; Data; Development; Dose; Effectiveness; Exclusion; Failure; Fc Receptor; Gene Frequency; Generations; Genes; Genetic Markers; Genetic Polymorphism; Genotype; Heterogeneity; Human; IgG Receptors; Immune; Ligands; Mediating; Monoclonal Antibodies; Outcome; Patients; Performance; Pharmaceutical Preparations; Population; Reagent; Regimen; Research Personnel; Research Project Grants; Resources; Rhesus; Role; Specimen; Therapeutic; Treatment Efficacy; Treatment outcome; Variant; biomarker identification; case control; design; experimental study; genetic association; genetic variant; improved; in vivo; nonhuman primate; predictive marker; programs; prospective; receptor; response; success; targeted agent

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.

项目摘要 - 应用研究项目 我们耗尽细胞的抗体资源在抗体数量，质量和多样性方面大大扩展 过去15年。我们现在建议使用一种新的应用研究方法来完善我们的资源 识别与治疗有效性相关的基因型。确定细胞排泄处理的成功 抗体具有与配体和触发效应器机制的能力。当这些功能中的任何一个 是次优的患者可能出现部分或没有耗尽的。在人类中，对治疗的反应差异 缺乏细胞的单克隆抗体与FC伽马受体中的特定多态性有关。 实际上，目前使用FC受体（FCR）和抗体靶基因生物标志物来鉴定患者 预计会对目标代理作出反应。虽然我们大多数动物对细胞止动疗法有反应，但这是 通常，在给定的实验中，一两个动物（约10％）不会具有有效的耗竭水平。 因为缺乏治疗成功的机制尚不确定，研究人员也不能 屏幕前研究动物，我们无法设计克服该障碍的抗体。为了充分利用我们的细胞 - 因此，耗尽资源，我们建议识别靶标和免疫效应子的遗传关联 具有细胞止血治疗成功的基因。我们的初步数据表明共同的分布分布 动物中的FCR等位基因效率低下与有效细胞耗竭。我们将使用候选基因病例对照 相关研究足够动力（n = 220-250）以识别与 治疗结果。鉴定可预测有效部署的生物标志物将具有 通过允许研究人员在研究或治疗之前筛查动物，对我们的资源产生直接影响 引发。重要的是，这些信息可用于采取纠正措施并提高治疗绩效， 通过排除较差的响应者或修改治疗方案。在下一个细胞动力的过程中 程序周期，遗传变异数据还将用于指导广泛功能抗体的设计 反对常见的目标变体。最后，从长远来看，此信息将用于设计新一代 对通常表达的FCR具有高亲和力的恒河-抗体。总而言之，正在提议识别 通过测序编码来自我们抗体或FC受体的靶配体的基因来测序相关的多态性。 具有不同细胞消耗结果的动物。这将通过1）生成生物标志物来提高我们的资源 与细胞枯竭疗法效率相关； 2）指导抗体的开发 常见目标变体；而且，从长远来看，3）导致新一代恒河馆的发展 通常表达的FCR具有较高识别的抗体。