Cancer Therapy Using Small Modular Immunopharmaceuticals

使用小型模块化免疫药物治疗癌症

• 批准号: 6832071
• 负责人: JEFFREY A LEDBETTER
• 金额: $ 10.67万
• 依托单位: TRUBION PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6832071
• 关键词: CD antigens; antibody receptor; biotechnology; cell line; cell mediated cytotoxicity; cellular immunity; chemical structure function; combination cancer therapy; cytokine; glycosylation; immunoglobulin E; immunologic substance development /preparation; immunopharmacology; immunotoxicity; intermolecular interaction; laboratory mouse; lymphoma; monoclonal antibody; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer pharmacology; neoplastic cell; nonhuman therapy evaluation; protein engineering; protein structure function

DESCRIPTION (provided by applicant): Antibody-based therapy for cancer treatment offers new hope and treatment options to patients. Based on the current success of several antibodies in treating cancer, monoclonal antibodies represent the fastest growing segment of the biopharmaceutical market. This application proposes to develop a novel small modular immunopharmaceutical (SMIP) approach to cancer therapy that is directed at Fc receptors for IgE. Of the several antibodies and antibody-based therapies that have been approved for marketing, all the antibodies belong to the classical IgG subtype. The mechanism by which many of these antibodies produce efficacy is not known. This application proposes to develop a novel small modular immunopharmaceutical (SMIP) that is directed at Fc receptors for IgE, SMIPs uses these receptors to recruit highly potent effector cells to attach and eliminate cancer cells. Trubion Pharmaceuticals, Inc. will engineer and develop SMIPs directed to CD20, a target already proven tobe vulnerable in the treatment of B cell lymphoma. Trubion will use engineered SMIPs as a path to morepotent biological agents that specifically target and kill cancer cells by cellular mediated mechanisms. Development of these synthetic SMIPs leverage the remarkable specificity, high affinity, and potency of IgE receptors. The engineering aspect of this application concerns remodeling IgE Fc-tailed SMIPs to better achieve improved potency, specificity, and selectivity for use as anticancer agents. The biology aspect concerns adapting highly potent cellular mechanisms of IgE action to eliminate cancer cells while avoiding the toxicity that could be associated with IgE Fc receptor activation. The overall goal of this application is to (i) demonstrate the ability of an engineered anti-CD20 SMIP to specifically treat lymphoma and (ii) establish the general usefulness of IgE Fc-tailed SMIP therapy. Synthetic IgE-based derivatives specific for human CD20will be cloned, expressed, and purified. After passing various biophysical tests for purity and specificity, SMIPs will be tested in vitro for various ADCC activities and evaluated in a cancer model in wildtype mice for their ability to inhibit and eliminate the growth of lymphomas that express CD20 on their surface.

描述（由申请人提供）：基于抗体的癌症治疗为患者提供了新的希望和治疗选择。基于目前几种抗体在治疗癌症方面的成功，单克隆抗体代表了生物制药市场增长最快的部分。本申请提出开发一种针对IgE的Fc受体的癌症治疗的新型小模块免疫药物（SMIP）方法。在已批准上市的几种抗体和基于抗体的疗法中，所有抗体都属于经典IgG亚型。许多这些抗体产生功效的机制尚不清楚。本申请提出开发一种新的小模块免疫药物（SMIP），其针对IgE的Fc受体，SMIP使用这些受体来募集高度有效的效应细胞以附着和消除癌细胞。 Trubion Pharmaceuticals，Inc.将设计和开发针对CD 20的SMIP，CD 20是一个已经被证明在治疗B细胞淋巴瘤中很脆弱的靶点。Trubion将使用工程SMIP作为一种更有效的生物制剂的途径，通过细胞介导的机制特异性靶向和杀死癌细胞。这些合成SMIP的开发利用了IgE受体的显著特异性、高亲和力和效力。 本申请的工程方面涉及重塑IgE Fc加尾SMIP以更好地实现用作抗癌剂的改善的效力、特异性和选择性。生物学方面涉及调整IgE作用的高效细胞机制以消除癌细胞，同时避免可能与IgE Fc受体活化相关的毒性。本申请的总体目标是（i）证明工程化抗CD20 SMIP特异性治疗淋巴瘤的能力和（ii）建立IgE Fc加尾SMIP疗法的一般有用性。将克隆、表达和纯化对人CD 20特异的合成IgE衍生物。在通过纯度和特异性的各种生物物理测试后，将在体外测试SMIP的各种ADCC活性，并在野生型小鼠的癌症模型中评估其抑制和消除在其表面上表达CD20的淋巴瘤生长的能力。