(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）是美国第六大常见恶性肿瘤，今年新发病例约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，并显著提高了生存率。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，大量的生物类似药和下一代抗cd20抗体处于临床开发的不同阶段，需要更好的抗体反应预测指标来优化治疗选择。我们的长期目标是开发基因策略，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治疗，具有复杂和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）。介导ADCC和CDC、FCGR3A和C1QA基因的遗传多态性预测利妥昔单抗治疗后的预后。我们发现了第三个基因CBLB，它在体外介导利妥昔单抗反应，尽管它在体内的意义尚未得到测试。体内实验测试人源化抗体的作用机制不容易用动物模型来解决，因为需要完整的免疫系统将人源化抗体本身识别为外源。因此，我们采用了一种新的遗传方法，使用带注释的人类样本来解决连接体内和体外反应的潜力，以表征和预测患者对利妥昔单抗的反应。我们假设FCGR3A、C1QA和CBLB这三个基因的遗传多态性决定了体外利妥昔单抗的反应，并准确预测了体内利妥昔单抗的反应。这项提议的具体目的是在体外测试这三种基因变化的影响，

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.