MUC16 Antibody Based Strategies for Imaging and Therapy

摘要 卵巢癌仍然是一个未得到满足的临床需求：三分之二的确诊患者 患者最终死于这种疾病，而新的治疗方法几乎没有取得任何进展 过去十年的递增捐款。MUC16的存在(它 编码CA125抗原)是卵巢高级别浆液性癌的标志 有其自身的不良后果和未被发现的生物学。这个项目利用了 MUC16相对选择性的性质，以解开复杂的生物学并暴露 用于治疗干预的癌症的基本弱点。在流传的同时 CA125已经成为治疗性抗体和抗独特型策略的靶点，这些 以前的干预并没有关注MUC16最近端的部分，也没有关注它的新奇部分 致病作用。 该项目有四个具体目标：具体目标1：询问糖基化 MUC16转化3T3细胞的依赖机制(S)及其增强作用 MUC16+人卵巢癌细胞的毒力研究具体目标2：利用MUC16 针对保留的“胞外结构域”的抗体和单链FCV构建物 开发卵巢癌的放射示踪剂和放射疗法。具体目标3：探索 并通过a)体外验证抗糖基化MUC16抗体的影响 研究，b)在荷瘤动物身上，c)启动人类抗肿瘤药物的开发 MUC16ab与尤里卡，导致d)人抗糖化的O相研究 MUC16抗体。具体目标4：与其他项目的互动，包括：援助 在MUC16疫苗开发(PR2)中，针对CAR T的第二代ab开发 信元(PR3)：以及在PR1和PR4之间共享最佳AB和FC机制。

ABSTRACT Ovarian cancer continues to represent an unmet clinical need: 2/3 of the diagnosed patients eventually die of the disease and new therapeutics has made almost no incremental contributions over the past decade. The presence of MUC16 (which encodes the CA125 antigen) is a hallmark of High Grade Serous Cancer of the Ovary with its own adverse outcome effect and undiscovered biology. This project exploits the relatively selective nature of MUC16 to unravel complex biology and expose fundamental cancer weaknesses for therapeutic intervention. While the circulating CA125 has been targeted by therapeutic antibody and anti-idiotype strategies, these prior interventions did not focus on the most proximal portions of MUC16 nor its novel pathogenic effects. The project has four specific aims: Specific Aim 1: To interrogate the glycosylation dependent mechanism(s) of MUC16 transformation in 3T3 cells and the enhanced virulence of MUC16 + human ovarian cancer cells. Specific Aim 2: To utilize MUC16 antibodies and single chain Fcv constructs targeting the retained “ectodomain” to develop radiotracers and radiotherapies for ovarian cancer. Specific Aim 3: To explore and validate the impact of anti-glycosylated MUC16 antibodies through a) in vitro studies, b) in tumor bearing animals, and c) initiate the development of human anti- MUC16 ab with Eureka, leading to d) a phase O study of a human anti-glycosylated MUC16 antibody. Specific Aim 4: Interactions with other projects including: assistance in MUC16 vaccine development (Pr2), Second generation ab development for CAR T cells (Pr3): and sharing of best ab with and Fc mechanisms between Pr 1 and Pr 4.