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 我们的细胞消耗抗体资源在抗体数量、质量和多样性方面都有了很大的扩展， 过去15年我们现正建议采用一种新的应用研究方法， 识别与治疗有效性相关的基因型。细胞耗竭治疗的成功取决于 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 是次优的，患者可能呈现部分消耗或没有消耗。在人类中，对治疗药物的不同反应 细胞消耗单克隆抗体与Fc γ受体的特异性多态性有关。 事实上，Fc受体（FcR）和抗体靶基因生物标志物目前用于鉴定患有以下疾病的患者： 对靶向药物有反应虽然我们的大多数动物对细胞耗竭治疗有反应， 通常情况下，在给定的实验中，一只或两只动物（约10%）将不会具有有效的消耗水平。 由于缺乏治疗成功的机制尚未确定， 我们也不能设计克服这一障碍的抗体。为了更好地利用我们的手机- 因此，我们建议确定靶点和免疫效应物的遗传关联， 细胞耗竭治疗成功的基因。我们的初步数据表明，共同的差异分布 FcR等位基因在具有无效与有效细胞耗竭的动物中。我们将使用候选基因病例对照 关联性研究，其具有足够的把握度（n= 220-250），以鉴定与以下各项相关的遗传标记： 治疗结果。预测有效消除的生物标志物的鉴定将具有 通过允许研究人员在研究或治疗之前筛选动物，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并提高治疗效果， 通过排除不良反应者或修改治疗方案。在下一次细胞耗竭过程中 在程序周期内，遗传变异数据也将用于指导广泛功能抗体的设计 针对常见的目标变体。最后，从长远来看，这些信息将用于设计新一代 对通常表达的FcRs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， 不同细胞耗竭结果的动物。这将通过1）生成生物标志物来改善我们的资源 与细胞耗竭治疗功效相关; 2）指导抗体的开发， 共同的目标变异;以及，从长远来看，3）导致新一代恒河猴的发展 通常表达的FcR具有上级识别的抗体。