An Anti-Cancer Immunoadhesin Made in Plants

描述（申请人提供）：肿瘤的生长和转移在很大程度上取决于新血管的发育，以向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剂的有吸引力的靶标。特别是一种蛋白质，肿瘤内皮标志物8（TEM 8），似乎只在成年人肿瘤血管内衬的内皮细胞中表达。最近的报告发现，TEM 8和IgG的Fc部分的融合物（TEM 8-Fc）在小鼠模型中是针对一系列人类肿瘤类型的有效抗癌剂。该I期项目的总体目标是使用快速和瞬时植物表达系统产生将增强与免疫效应细胞上的某些受体的结合的TEM 8-Fc形式。受体结合的改善将通过重组蛋白的糖型和氨基酸工程实现。然后，我们将检验以下假设：TEM 8-Fc的抗肿瘤活性与其介导表达表面TEM 8的细胞的抗体依赖性细胞毒性（ADCC）的能力有关。ADCC活性比较之后将比较裸鼠异种移植模型中的抗肿瘤活性。转基因植物是大规模生产抗体和其他治疗性蛋白质的一个有前途的平台，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非常低的商品成本和安全性，因为植物不能被哺乳动物病毒和朊病毒感染。烟草是一种不用于人类食物链的植物，在烟草中生产避免了对食品或饲料中偶然存在治疗性蛋白质的担忧。此外，烟草每英亩可生产的蛋白质数量远远超过玉米等种子作物的可能性。然而，纯化的成本与哺乳动物细胞培养中产生的蛋白质的成本相似。长期目标是将TEM 8-Fc开发成一种高效、安全和经济的治疗方法，用于广泛的转移性癌症。公共卫生相关性：需要新的和更有效的癌症治疗方法。该项目将研究一种抑制血管生成和肿瘤生长的新型重组蛋白的作用机制，并应确定对蛋白质的修饰，使其在较低剂量下更有效。这种蛋白质在植物中的表达将允许高度经济、大规模和安全的生产，使得使用1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.