Enhanced Efficacy of MUC16 directed antibodies through modification of the Fc domain

项目摘要 卵巢癌仍然是一个未满足的临床需求，因为三分之二的确诊患者最终死亡 在过去的十年里，这种疾病的研究和新的治疗方法几乎没有产生什么影响。在本提案中，我们将利用 一组新的抗MUC 16抗体和我们对Fc γ受体（Fc γ R）途径的广泛了解 有助于对治疗性抗体的抗肿瘤活性进行临床前研究， 抗MUC 16抗体用于治疗卵巢癌。MUC 16是一个有吸引力的基于抗体的靶点。 由于其在大多数卵巢癌组织中的组织特异性过表达， 癌的我们已经获得了一组新的针对MUC 16胞外部分的单克隆抗体（mAb）， 并将表征这些单克隆抗体介导抗肿瘤活性的体内机制， 表达人MUC 16同基因和自发肿瘤模型。在目标1中，我们将确定 抗MUC 16抗体为了其最佳体内抗肿瘤活性所需的Fc β R相互作用，通过使用Fc 突变体和特异性缺乏Fc γ R的菌株。我们将利用这些结果，并利用我们独特的Fc γ R菌株- 人源化小鼠作为开发人源化Fc工程化抗人MUC 16抗体的临床前平台 优化以增强体内抗肿瘤活性。在目标2中，我们将利用我们最近的发现， 细胞毒性抗肿瘤抗体的施用刺激抗肿瘤细胞免疫应答， 确定抗MUC 16 mAb与免疫调节抗体组合是否也刺激细胞增殖， 抗肿瘤免疫应答协同增强抗肿瘤免疫。对于这些研究，我们将重点关注 激动性抗-CD 40和拮抗性抗-CTLA-4抗体，其已经被Fc工程化以获得最佳的抗-CD 40和抗-CTLA-4抗体， 在体内介导其作用的适当Fc γ R途径的参与。通过测试人源化抗- MUC 16抗体在临床前体内模型中表达人Fc β R途径和人MUC 16， 作为一个目标，拟议的研究对人类患者具有高度的可转化性，如果成功，可能会导致 开发用于试验的特异性临床候选抗体。

Project Summary Ovarian cancer continues to represent an unmet clinical need, as two-thirds of diagnosed patients eventually die of the disease and new therapeutics have made little impact over the past decade. In this proposal, we will utilize a novel panel of anti-MUC16 antibodies and our extensive knowledge of how Fc-receptor (FcR) pathways contribute to the anti-tumor activities of therapeutic antibodies to perform a preclinical study for the optimization of anti-MUC16 antibodies for the treatment of ovarian cancer. MUC16 is an attractive target for antibody-based immune therapies for ovarian cancer because of its tissue-specific overexpression in most of the ovarian cancers. We have obtained a novel panel of monoclonal Abs (mAbs) against the extracellular portion of MUC16, and will characterize the in vivo mechanisms by which these mAbs mediate anti-tumor activities in novel syngeneic and spontaneous tumor models that express human MUC16. In Aim 1, we will determine the specific FcR interactions required by anti-MUC16 antibodies for their optimal in vivo anti-tumor activities by using Fc mutants and strains specifically lacking FcRs. We will exploit these results and utilize our unique strain of FcR- humanized mice as a preclinical platform to develop humanized Fc-engineered anti-human MUC16 antibodies optimized for augmented in vivo anti-tumor activity. In Aim 2, we will exploit our recent finding that passive administration of cytotoxic anti-tumor antibodies stimulates and anti-tumor cellular immune reponses to determine whether combining anti-MUC16 mAb with immunomodulatory antibodies that also stimulate cellular anti-tumor immune responses synergistically enhances anti-tumor immunity. For these studies, we will focus on agonistic anti-CD40 and antagonist anti-CTLA-4 antibodies that have been Fc engineered for optimal engagement of the appropriate FcR pathways that mediate their effects in vivo. By testing humanized anti- MUC16 antibodies in a preclinical in vivo models expressing the human FcR pathways and human MUC16 as a target, the proposed research is highly translatable to human patients, and if successful, may lead to the development of specific clinical candidate antibodies for trials.