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

描述（由申请人提供）：自1997年以来，靶向肿瘤相关抗原（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对几种白血病和淋巴瘤的显着疗效和效力。我们建议在这项I期SBIR研究中，确定是否可行开发一个基于工程设计的新型人类支架MICA的平台，通过产生特异性免疫突触来靶向和促进特异性癌细胞的杀伤。天然免疫系统的NK细胞和某些t细胞通过持续监视表达表面MICA或MICB的细胞来保护宿主免受恶性敌人的侵害，MICA或MICB是细胞对宿主健康构成威胁的指标。一旦这些先天免疫的效应细胞检测到一个被膜结合的MIC蛋白修饰的细胞，它们就攻击并摧毁这个修饰的、有威胁的细胞。这些威胁包括恶性肿瘤；但许多癌细胞表达的MICA水平不足以招募效应细胞。许多高级别恶性细胞在细胞内捕获MIC蛋白或分泌蛋白酶，将MIC蛋白从其表面切割，清除求救信号并使其能够逃避先天免疫。因此，尽管癌细胞是危险的，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MICA装饰其表面来克服这种恶性细胞的逃逸。可溶MICA特异性靶向在恶性细胞表面唯一表达的TAA，将通过肠外给药。这种新颖的方法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”。创新之处在于将这种由先天免疫系统自然部署的人类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，迅速杀死目标细胞。在此，我们建议将这些平台技术和概念集中在一个原型和重要的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中过表达的致癌蛋白。我们打算证明在体外特异性杀伤表达FGFR3的人类细胞。

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.