An Anti-Cancer Immunoadhesin Made in Plants

描述（由申请人提供）：肿瘤的生长和转移在很大程度上依赖于新血管的发育，为快速生长和分裂的细胞提供食物和氧气。参与血管生成的蛋白质是新的癌症治疗的有吸引力的靶点。有一种蛋白质，肿瘤内皮标记物8 (TEM8)，似乎只在成人肿瘤血管内皮细胞中表达。最近的一份报告发现，TEM8和IgG的Fc部分的融合（TEM8-Fc）在小鼠模型中是一种有效的抗癌剂，可以对抗一系列人类肿瘤类型。这个I期项目的总体目标是使用快速和瞬时植物表达系统，生产TEM8-Fc形式，该形式将增强与免疫效应细胞上某些受体的结合。受体结合的改进将通过重组蛋白的糖型和氨基酸工程来实现。然后，我们将验证TEM8- fc的抗肿瘤活性与其介导表达表面TEM8的细胞的抗体依赖性细胞毒性（ADCC）的能力有关的假设。比较ADCC活性之后，将比较裸鼠异种移植模型的抗肿瘤活性。转基因植物是大规模生产抗体和其他治疗性蛋白质的有希望的平台，用于治疗严重和危及生命的疾病，包括癌症。在生物反应器中使用植物而不是转基因动物细胞的优点包括产品成本极低，而且由于植物不能被哺乳动物病毒和朊病毒感染而具有安全性。烟草是一种不用于人类食物链的植物，它的生产避免了人们对食品或饲料中意外存在治疗性蛋白质的担忧。此外，每英亩烟草可生产的蛋白质量远远超过玉米等种子作物。然而，纯化的成本与哺乳动物细胞培养中产生的蛋白质相似。长期目标是将TEM8-Fc发展成为一种高效、安全和经济的治疗多种转移性癌症的药物。公共卫生相关性：需要新的和更有效的癌症治疗方法。该项目将研究一种新型重组蛋白的作用机制，该蛋白抑制血管生成和肿瘤生长，并应确定对蛋白质的修饰，使其在低剂量下更有效。这种蛋白在植物中的表达将允许高度经济、大规模和安全的生产，使使用一克或更大剂量的这种重组蛋白的癌症治疗更加可行。

DESCRIPTION (provided by applicant): The growth and metastasis of tumors depends, to a large extent, on the development of new blood vessels to supply food and oxygen to rapidly growing and dividing cells. Proteins involved in angiogenesis are attractive targets for new cancer therapeutics. One protein in particular, tumor endothelial marker 8 (TEM8), appears to be expressed exclusively, in adults, in the endothelial cells lining tumor blood vessels. A recent report found that a fusion of TEM8 and the Fc portion of IgG (TEM8-Fc) was a potent anti-cancer agent in a mouse model against a range of human tumor types. The overall goal of this Phase I project is to produce, using a rapid and transient plant expression system, forms of TEM8-Fc that will have enhanced binding to certain receptors on immune effector cells. Improvements in receptor binding will be achieved through both glycoform and amino acid engineering of the recombinant protein. We will then test the hypothesis that the anti-tumor activity of TEM8-Fc is related to its ability to mediate antibody dependent cellular cytotoxicity (ADCC) of cells expressing surface TEM8. Comparisons of ADCC activity will be followed by comparisons of anti-tumor activity in a nude mouse xenotransplantation model. Transgenic plants are a promising platform for the large-scale production of antibodies and other therapeutic proteins for treating serious and life-threatening conditions, including cancer. The advantages of using plants, rather than genetically modified animal cells in bioreactors, include very low cost of goods, and safety, due to the inability of plants to be infected with mammalian viruses and prions. Production in tobacco, a plant not used in the human food chain, avoids concerns about adventitious presence of therapeutic proteins in food or feed. In addition, the amount of protein that can be produced per acre with tobacco far exceeds what is possible with a seed crop like corn. Costs of purification, however, are similar to that of proteins produced in mammalian cell culture. The long-term goal is to develop TEM8-Fc into a highly effective, safe and economical treatment for a wide range of metastatic cancers. PUBLIC HEALTH RELEVANCE: New and more effective therapies for cancer are needed. This project would examine the mechanism of action of a novel recombinant protein that inhibits angiogenesis and growth of tumors, and should identify modifications to the protein that will make it even more effective at lower doses. Expression of this protein in plants will allow highly economical, large scale and safe production, making cancer therapy using dosages of a gram or greater of this recombinant protein much more available.