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

通过修饰 Fc 结构域增强 MUC16 定向抗体的功效

基本信息

批准号：
8933343
负责人：
JEFFREY Victor RAVETCH
金额：
$ 31.55万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8933343
关键词：
Adjuvant Antibodies Antigen-Antibody Complex Antigens Breast Cancer Cell CA-125 Antigen Cancer Model Clinical Combined Modality Therapy Dependence Development Diagnosis Disease ERBB2 gene Engineering Enhancing Antibodies Epitopes Fc Receptor Fc domain Genes Human Immune Immune response Immune system Immunoglobulin G Immunologics Immunosuppressive Agents Immunotherapy Knowledge Lead Link Lymphoma MS4A1 gene Malignant Neoplasms Malignant neoplasm of ovary Mediating Modeling Modification Mus Pathway interactions Patients Research Roche brand of trastuzumab Surface System TNFRSF5 gene Testing Therapeutic Therapeutic antibodies Tissues Transgenic Mice Trastuzumab Tumor Antibodies Tumor Antigens Tumor Immunity Work adaptive immunity antitumor effect base cancer cell cytotoxic cytotoxicity extracellular improved in vivo in vivo Model killings mouse model mutant neoplastic cell novel novel therapeutics overexpression pre-clinical preclinical study response rituximab tool tumor

项目摘要

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.

项目摘要卵巢癌仍然是一个未得到满足的临床需求，因为三分之二的确诊患者最终死亡。在过去的十年里，这种疾病和新的治疗方法几乎没有起到什么作用。在这个提案中，我们将利用一组新的抗MUC16抗体和我们对Fc受体(FcR)途径的广泛了解有助于抗肿瘤活性的治疗性抗体进行临床前研究的优化用于治疗卵巢癌的抗MUC16抗体。MUC16是基于抗体的有吸引力的靶点卵巢癌的免疫治疗，因为它在大多数卵巢组织中过表达癌症。我们获得了一组新的抗MUC16胞外部分的单抗，并将表征这些单抗在体内介导抗肿瘤活性的机制表达人MUC16的同源和自发肿瘤模型。在目标1中，我们将确定具体的抗MUC16抗体体内最佳抗肿瘤活性所需的Fc--R相互作用缺乏FcR的突变体和菌株。我们将利用这些结果，并利用我们独特的FCR株- 人源化小鼠作为临床前平台制备人源化Fc工程抗人MUC16抗体针对增强体内抗肿瘤活性进行了优化。在目标2中，我们将利用我们最近的发现，即被动给予细胞毒性抗肿瘤抗体刺激和抗肿瘤细胞免疫反应确定联合抗MUC16单抗和免疫调节抗体是否也刺激细胞抗肿瘤免疫应答协同增强抗肿瘤免疫。对于这些研究，我们将重点放在激动型抗CD40抗体和拮抗型抗CTLA-4抗体已被Fc设计为最佳参与调节其体内效应的适当的FcR通路。通过测试人性化的反表达人FcR通路和人MUC16 AS的临床前体内模型中的MUC16抗体作为一个目标，拟议的研究对人类患者具有高度的可译性，如果成功，可能会导致用于试验的特异性临床候选抗体的开发。