(PQD5) A novel genetic strategy to predict efficacy of anti-CD20 antibodies

描述（由申请人提供）：非霍奇金淋巴瘤（NHL）是美国第六常见的恶性肿瘤，今年新增约7万例。利妥昔单抗是一种靶向B细胞上CD20抗原的单克隆抗体，用于治疗大多数NHL患者，并显着提高了生存率。然而，并非所有患者最初都对利妥昔单抗有反应，许多其他患者最终会产生耐药性。正因为如此，大量的生物仿制药和下一代抗CD20抗体处于临床开发的不同阶段，需要更好的抗体应答预测因子来优化治疗选择。我们的长期目标是制定遗传策略，为个体患者量身定制治疗选择。这种遗传方法特别适用于免疫疗法，其中复杂且遗传可变的免疫系统介导药物反应。利妥昔单抗介导的细胞死亡的两种机制是抗体依赖性细胞介导的细胞毒性（ADCC）和补体依赖性细胞毒性（CDC）。遗传多态性基因介导的ADCC和CDC，FCGR3A和C1QA，预测利妥昔单抗治疗后的结果。我们已经发现了第三个基因，CBLB，它介导利妥昔单抗在体外的反应，虽然它在体内的意义是未经测试的。测试人源化抗体的作用机制的体内实验不容易用动物模型解决，因为所需的完整免疫系统将人源化抗体本身识别为外来物。因此，我们采用了一种新的遗传方法，使用注释的人类样本，以解决潜在的连接在体内和体外反应，以表征和预测患者对利妥昔单抗的反应。我们假设，遗传多态性在三个基因，FCGR3A，C1QA和CBLB，确定利妥昔单抗反应在体外，并准确预测利妥昔单抗反应在体内。这项提议的具体目的是在体外测试这三个基因的改变的效果， 使用CDC和ADCC测定，以测量每个基因对利妥昔单抗应答的影响。然后，我们将测试一个大型的弥漫性大B细胞淋巴瘤（DLBCL）患者的临床试验队列，以测量体内三个基因多态性的影响。我们将比较体外和体内结果，以验证体外系统。最后，我们将在我们的体外系统中测试新的抗CD20抗体，以测量FCGR3A，C1QA和CBLB多态性与利妥昔单抗相比的影响。通过这种方式，这些药物的未来临床使用可以基于患者基因型进行个性化，优化抗CD20抗体的使用以改善临床结局。

DESCRIPTION (provided by applicant): Non-Hodgkin lymphoma (NHL) is the sixth most common malignancy in the U.S., with ~70,000 new cases this year. Rituximab, a monoclonal antibody targeting the CD20 antigen on B-cells, is used to treat the majority of NHL patients, and has improved survival rates significantly. However, not all patients respond to rituximab initially, and many other patients eventually develop resistance. Because of this, a plethora of biosimilar and next-generation anti-CD20 antibodies are in various stages of clinical development, necessitating better predictors of antibody response to optimize choice of therapy. Our long-term objective is to develop genetic strategies to tailor therapy choices to individual patients. This genetic approach is particularly pertinent for immunotherapies, with a complex and genetically variable immune system mediating drug response. Two mechanisms of rituximab-mediated cell death are antibody-dependent cell mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Inherited polymorphisms in genes mediating ADCC and CDC, FCGR3A and C1QA, predict outcomes after rituximab treatment. We have discovered a third gene, CBLB, which mediates rituximab response in vitro, although its significance in vivo is untested. In vivo experiments to test mechanism of action of humanized antibodies are not easily addressed with animal models, since the intact immune system that is required recognizes the humanized antibody itself as foreign. Therefore, we employ a novel genetic approach using annotated human samples to address the potential for linking in vivo and in vitro responses to characterize and predict response to rituximab in patients. We hypothesize that inherited polymorphisms in three genes, FCGR3A, C1QA, and CBLB, determine rituximab response in vitro, and accurately predict rituximab response in vivo. The specific aims of this proposal are to test the effect of alterations in these three genes in vitro, using CDC and ADCC assays, to measure the effect of each gene on rituximab response. We will then test a large clinical trial cohort of diffuse large B-cell lymphoma (DLBCL) patients to measure the effect of polymorphisms in the three genes in vivo. We will compare in vitro and in vivo results to validate the in vitro system. Finally, we will test newer anti-CD20 antibodies usin our in vitro system, to measure effects of FCGR3A, C1QA, and CBLB polymorphisms compared with rituximab. In this way, future clinical use of these agents can be personalized based on patient genotype, optimizing use of anti-CD20 antibodies for improved clinical outcomes.