Monoclonal Antibody Therapy Induction of Adaptive Immunity

单克隆抗体治疗诱导适应性免疫

• 批准号: 7382864
• 负责人: Louis M. Weiner
• 金额: $ 20.52万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-24 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382864
• 关键词: Affect; Affinity; Animals; Antibodies; Antibody Therapy; Antigen Presentation; Antigens; Apoptosis; Autologous; Binding; CD8B1 gene; Cancer Detection; Cells; Clinic; Clinical; Colorectal Cancer; Cytotoxic T-Lymphocytes; Data; Development; Diagnosis; Disease; Disease regression; Dose; ERBB2 gene; Engineering; Event; Exhibits; Fc Receptor; Flow Cytometry; Generations; Goals; Human; Human Engineering; IgG1; Immune; Immune response; Immunity; Immunocompetent; Immunodeficient Mouse; Immunoglobulin G; In Vitro; Interleukin-2; Lead; Link; Lymphoma; Malignant Neoplasms; Mediating; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mouse Strains; Mus; Natural Killer Cells; Patients; Peripheral Blood Lymphocyte; Property; Reagent; Recombinants; Research; Resistance; Schedule; Series; Serum; Signal Transduction; Splenocyte; Structure; T-Lymphocyte; Techniques; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Translating; Translational Research; Tumor Antibodies; Tumor Antigens; United States National Institutes of Health; Variant; Work; antibody engineering; antibody-dependent cell cytotoxicity; clinically relevant; cytokine; human cancer mouse model; immunodeficient mouse model; improved; in vivo; interest; malignant breast neoplasm; outcome forecast; passive antibodies; programs; response; tumor; tumor growth

DESCRIPTION (provided by applicant): This proposal is responsive to PA-06321, Cross-Disciplinary Translational Research At NIH (R21). Optimization of the capacity of monoclonal antibodies to mediate antibody-dependent cellular cytotoxicity (ADCC) should contribute to clinical activity. We are employing the techniques of antibody engineering to generate antibodies with improved ADCC properties that permit us to test two broad hypotheses: 1) antibodies with high affinity for a tumor antigen and for cellular Fc receptors will exhibit highly efficient ADCC and will mediate potent in vivo anti-tumor effects; and 2) such antibodies will induce adaptive immune responses that contribute to tumor efficacy. Preliminary data indicate that the capacity of recombinant anti-HER2/neu IgG antibodies to promote in vitro ADCC is related to their affinities for HER2/neu. Using other support we are preparing engineered human IgG1 monoclonal antibodies that bind to human HER2/neu and to Fc3R with varying affinities, to assess the in vivo anti-tumor effects of engineered human IgG1 monoclonal antibodies that bind to human HER2/neu and human Fc3RIII with varying affinities. Here we propose to test the hypothesis that treatment-induced in vivo ADCC promotes antigen presentation and initiates an adaptive immune response that contributes to tumor control and can be further amplified and prolonged by promoting antigen presentation, T cell costimulation and proliferation, and the expansion of antigen-specific cytotoxic T-cells. Specific Aim 1 is to determine the ability of engineered human IgG1 monoclonal antibodies that bind to human HER2/neu and to Fc3R to induce adaptive immune responses against human HER2/neu and to tumors expressing that antigen. The studies proposed here will lead to the creation of antibodies that mediate maximal ADCC and promote the induction of immune responses directed against autologous tumors in immunocompetent subjects. We have created an immunocompetent mouse strain that is transgenic for human HER2/neu to permit study of the link between ADCC and the induction of adaptive immune responses. Specific Aim 2 is to amplify monoclonal antibody-induced anti-tumor immune responses by combining anti-HER2/neu antibody therapy with anti-CTLA4, or other immunomodulatory approaches. This work will define the ability of passive antibody therapy to induce clinically relevant, adaptive anti-cancer immune responses and will define new avenues of treatment for patients with HER2/neu-positive tumors. The goal of this proposal is to use anti-HER2/neu monoclonal antibody therapy to stimulate immune responses against HER2/neu-expressing cancers. This work will identify strategies that amplify and sustain the anti-tumor immune response, and the results will be applicable to the general field of antibody therapy. A candidate antibody for clinical development will emerge, as will generally useful information regarding the structural features of antibodies that contribute to ADCC and in vivo efficacy.

描述（由申请人提供）：本提案响应PA-06321， NIH跨学科转化研究（R21）。优化单克隆抗体介导抗体依赖性细胞毒性（ADCC）的能力有助于临床活性。我们正在使用抗体工程技术来产生具有改进ADCC特性的抗体，这使我们能够测试两个广泛的假设：1)对肿瘤抗原和细胞Fc受体具有高亲和力的抗体将表现出高效的ADCC，并将介导有效的体内抗肿瘤作用；2)这些抗体会诱导适应性免疫反应，有助于肿瘤的疗效。初步数据表明，重组抗HER2/neu IgG抗体促进体外ADCC的能力与其对HER2/neu的亲和力有关。利用其他支持，我们正在制备与人HER2/neu和Fc3R具有不同亲和力的工程化人IgG1单克隆抗体，以评估与人HER2/neu和人Fc3RIII具有不同亲和力的工程化人IgG1单克隆抗体的体内抗肿瘤效果。在这里，我们提出验证治疗诱导的体内ADCC促进抗原呈递并启动有助于肿瘤控制的适应性免疫反应的假设，并且可以通过促进抗原呈递、T细胞共刺激和增殖以及抗原特异性细胞毒性T细胞的扩增而进一步扩增和延长。特异性目的1是确定与人HER2/neu和Fc3R结合的工程化人IgG1单克隆抗体诱导针对人HER2/neu和表达该抗原的肿瘤的适应性免疫反应的能力。这里提出的研究将导致产生抗体，介导最大的ADCC，并促进诱导免疫应答，直接针对免疫功能正常的受试者的自体肿瘤。我们已经创造了一种具有免疫能力的小鼠品系，它是人类HER2/neu转基因的，可以研究ADCC和诱导适应性免疫反应之间的联系。特异性目的2是通过联合抗her2 /新抗体治疗与抗ctla4或其他免疫调节方法，扩增单克隆抗体诱导的抗肿瘤免疫应答。这项工作将确定被动抗体治疗诱导临床相关的适应性抗癌免疫反应的能力，并将为HER2/新阳性肿瘤患者确定新的治疗途径。该建议的目标是使用抗HER2/neu单克隆抗体治疗来刺激针对表达HER2/neu的癌症的免疫反应。这项工作将确定放大和维持抗肿瘤免疫反应的策略，其结果将适用于抗体治疗的一般领域。一种用于临床开发的候选抗体将会出现，有关ADCC抗体结构特征和体内疗效的一般有用信息也将出现。