DIVERSIFYING MICA TO CREATE TARGETED ADAPTERS TO RECRUIT AND ACTIVATE NK CELLS TO

使云母多样化以创建有针对性的适配器来招募和激活 NK 细胞

• 批准号: 8455819
• 负责人: David William Martin
• 金额: $ 31.61万
• 依托单位: AVIDBIOTICS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2014-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8455819
• 关键词: Accounting; Achievement; Affinity; Antibodies; Attention; Avidity; Binding; Bispecific Antibodies; CD94 Antigen; Cancer Etiology; Cancerous; Cell surface; Cell-Mediated Cytolysis; Cells; Cleaved cell; Clinical Trials; Cytolysis; Distress; Effector Cell; Engineering; Enzymes; Fc domain; Grant; Health; Human; Immune; Immune system; Immunoglobulin Fragments; Immunologics; Immunotherapy; In Vitro; Killer Cells; Ligands; Liquid substance; MICA protein; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mammals; Mediating; Membrane; Mica; Monoclonal Antibodies; Multiple Myeloma; Natural Immunity; Natural Killer Cells; Nature; Oncogenic; Oncolytic; Peptide Hydrolases; Phage Display; Pharmaceutical Preparations; Phase; Protein Engineering; Proteins; Publishing; Recruitment Activity; Sales; Signal Transduction; Small Business Innovation Research Grant; Staging; Stress; Surface; Surface Antigens; Synapses; System; T-Lymphocyte; Technology; Therapeutic; Therapeutic antibodies; Tumor Antigens; Virus; arm; base; cancer cell; cell killing; clinical efficacy; fibroblast growth factor receptor 3; innovation; killings; leukemia/lymphoma; neoplastic cell; novel; novel strategies; oncolysis; public health relevance; receptor; scaffold; tumor

DESCRIPTION (provided by applicant): Monoclonal antibodies targeting tumor associated antigens (TAA's) have since 1997, provided safe and efficacious human cancer therapeutics. More recently, bispecific antibodies or bispecific antibody fragments that promote immunologic synapses between cells of the innate immune system and malignant cells have shown in clinical trials remarkable efficacy and potency against several leukemias and lymphomas. We propose in this Phase I SBIR study to determine whether it is feasible to develop a platform based on engineering a novel human scaffold, MICA, to target and promote killing of specific cancer cells by generating specific immunologic synapses. NK cells and certain T-cells of the innate immune system protect the host from the malignant enemy within by constant surveillance for cells expressing surface MICA or MICB, indicators that the cell is a threat to the health of the host. Once such effector cells of the innate immunity detect a cell decorated by a membrane-bound MIC protein, they attack and destroy the decorated, threatening cell. Such threats include malignancies; but many cancerous cells do not express a level of MICA sufficient to recruit the effector cells. Many high grade malignant cells trap MIC protein intracellularly or secrete proteases that cleave the MIC protein from their surface, clearing the distress signal and enabling escape from innate immunity. Thus, in spite of being dangerous and threatening host survival, cancer cells can break through the surveillance by manipulating surface expression of MIC proteins. We propose to overcome this escape of malignant cells by decorating their surfaces with MICA from outside. Soluble MICA targeted specifically to TAA's expressed uniquely on the malignant cell surface would be administered parenterally. Such a novel approach enables an adaptive use of Nature's potent innate immunity to override the evolved, nefarious mechanism of cancer escape---"innate immunotherapy". The innovation lies in the conversion of this human MICA scaffold naturally deployed by the innate immune system into an immune "adaptor" that specifically binds malignant cells and thereby recruits and activates innate immunity effector cells expressing the receptor for MICA, NKG2D, to promptly kill the targeted cell. We propose herein to focus these platform technologies and concepts on a prototypic and important TAA, Fibroblast Growth Factor Receptor-3 (FGFR3), an oncogenic protein over expressed on most human bladder cancers and many multiple myeloma cells. We intend to demonstrate in vitro specific killing of human cells expressing FGFR3.

描述（由申请人提供）：自 1997 年以来，针对肿瘤相关抗原 (TAA) 的单克隆抗体提供了安全有效的人类癌症治疗方法。最近，促进先天免疫系统细胞和恶性细胞之间的免疫突触的双特异性抗体或双特异性抗体片段在临床试验中显示出针对多种白血病和淋巴瘤的显着功效和效力。我们建议在这项 I 期 SBIR 研究中确定开发一个基于新型人体支架 MICA 的平台是否可行，通过生成特定的免疫突触来靶向和促进杀死特定的癌细胞。 NK 细胞和先天免疫系统的某些 T 细胞通过持续监视表达表面 MICA 或 MICB 的细胞（表明该细胞对宿主健康构成威胁），保护宿主免受内部恶性敌人的侵害。一旦先天免疫的效应细胞检测到由膜结合 MIC 蛋白装饰的细胞，它们就会攻击并摧毁装饰的威胁细胞。此类威胁包括恶性肿瘤；但许多癌细胞不表达足以招募效应细胞的 MICA 水平。许多高级恶性细胞将 MIC 蛋白捕获在细胞内或分泌蛋白酶，将 MIC 蛋白从其表面裂解下来，清除求救信号并逃避先天免疫。因此，尽管癌细胞存在危险并威胁宿主的生存，但它们可以通过操纵 MIC 蛋白的表面表达来突破监视。 我们建议通过从外部用云母装饰恶性细胞的表面来克服恶性细胞的逃逸。专门针对恶性细胞表面独特表达的 TAA 的可溶性 MICA 将通过肠胃外给药。这种新颖的方法使得能够适应性地利用大自然强大的先天免疫来克服进化的、邪恶的癌症逃逸机制——“先天免疫疗法”。 创新在于将先天免疫系统自然部署的这种人类MICA支架转化为免疫“适配器”，特异性结合恶性细胞，从而招募和激活表达MICA受体NKG2D的先天免疫效应细胞，以迅速杀死恶性细胞。目标细胞。我们在此建议将这些平台技术和概念集中在原型和重要的TAA上，即成纤维细胞生长因子受体3（FGFR3），这是一种在大多数人类膀胱癌和许多多发性骨髓瘤细胞上过度表达的致癌蛋白。我们打算证明对表达 FGFR3 的人类细胞的体外特异性杀伤。