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:
- 金额:$ 31.55万
- 依托单位:
- 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:
- 关键词:AdjuvantAntibodiesAntigen-Antibody ComplexAntigensBreast Cancer CellCA-125 AntigenCancer ModelClinicalCombined Modality TherapyDependenceDevelopmentDiagnosisDiseaseERBB2 geneEngineeringEnhancing AntibodiesEpitopesFc ReceptorFc domainGenesHumanImmuneImmune responseImmune systemImmunoglobulin GImmunologicsImmunosuppressive AgentsImmunotherapyKnowledgeLeadLinkLymphomaMS4A1 geneMalignant NeoplasmsMalignant neoplasm of ovaryMediatingModelingModificationMusPathway interactionsPatientsResearchRoche brand of trastuzumabSurfaceSystemTNFRSF5 geneTestingTherapeuticTherapeutic antibodiesTissuesTransgenic MiceTrastuzumabTumor AntibodiesTumor AntigensTumor ImmunityWorkadaptive immunityantitumor effectbasecancer cellcytotoxiccytotoxicityextracellularimprovedin vivoin vivo Modelkillingsmouse modelmutantneoplastic cellnovelnovel therapeuticsoverexpressionpre-clinicalpreclinical studyresponserituximabtooltumor
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 (FcR) 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
FcR interactions required by anti-MUC16 antibodies for their optimal in vivo anti-tumor activities by using Fc
mutants and strains specifically lacking FcRs. We will exploit these results and utilize our unique strain of FcR-
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 FcR pathways that mediate their effects in vivo. By testing humanized anti-
MUC16 antibodies in a preclinical in vivo models expressing the human FcR 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(FcR)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FcR的突变体和菌株。我们将利用这些结果,并利用我们独特的FCR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FcR通路。通过测试人性化的反
表达人FcR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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JEFFREY Victor RAVETCH其他文献
JEFFREY Victor RAVETCH的其他文献
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{{ truncateString('JEFFREY Victor RAVETCH', 18)}}的其他基金
Integrating innate and adaptive pathways in vaccine responses
将先天和适应性途径整合到疫苗反应中
- 批准号:
10265794 - 财政年份:2020
- 资助金额:
$ 31.55万 - 项目类别:
Molecular mechanisms of antibody-mediated immunotherapies
抗体介导的免疫疗法的分子机制
- 批准号:
10368931 - 财政年份:2016
- 资助金额:
$ 31.55万 - 项目类别:
Molecular mechanisms of antibody-mediated immunotherapies
抗体介导的免疫疗法的分子机制
- 批准号:
10684073 - 财政年份:2016
- 资助金额:
$ 31.55万 - 项目类别:
Molecular mechanisms of antibody-mediated immunotherapies
抗体介导的免疫疗法的分子机制
- 批准号:
8940844 - 财政年份:2016
- 资助金额:
$ 31.55万 - 项目类别:
Molecular mechanisms of antibody-mediated immunotherapies
抗体介导的免疫疗法的分子机制
- 批准号:
10518790 - 财政年份:2016
- 资助金额:
$ 31.55万 - 项目类别:
Molecular mechanisms of antibody-mediated immunotherapies
抗体介导的免疫疗法的分子机制
- 批准号:
9888968 - 财政年份:2016
- 资助金额:
$ 31.55万 - 项目类别:
Integrating innate and adaptive pathways in vaccine responses
将先天和适应性途径整合到疫苗反应中
- 批准号:
10595522 - 财政年份:2014
- 资助金额:
$ 31.55万 - 项目类别:
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