NOVEL THERAPY FOR CANDIDA ALBICANS INFECTION

严重的黏膜白色念珠菌是免疫抑制患者发病和死亡的主要原因，需要毒性较低的治疗药物。我们的合作者Luciano Polonelli博士已经制备了一些酵母杀手毒素(KT)抗独特型抗体(KT-ID Mab)，这些抗体模拟了本土杀手毒素对念珠菌和肺孢子虫的细胞毒活性。天然KT不能使用，因为它不稳定，具有免疫原性，在中性pH下活性大大降低。KT-ID单抗局部应用于啮齿动物模型，对阴道念珠菌病和肺部卡氏肺孢子虫感染均有效。Panorama Research Inc.(PRI)的植物分子生物学部门开创了在转基因植物中生产分泌型LGA抗体的专利方法。SIgA植物抗体是黏膜使用的首选抗体治疗形式。本项目的总体目标是制备一种SIgA形式的这种抗ID，作为一种经济、稳定、治疗白色念珠菌感染的药物。在第一阶段，我们将使用具有杀灭念珠菌活性的生物活性单链抗体构建分泌型IgA植物体表达盒。这些将被用来通过粒子轰击转化烟草，并将选择表达组装的SIgA的植物。接下来，我们将用体外杀菌实验证明纯化的抗ID-SIgA植物抗体的细胞毒活性。该项目的成功完成将展示一种对抗疑难粘膜病原体的通用专利方法。建议的商业应用：严重的粘膜念珠菌病感染是一个主要问题。一种新的治疗方法代表着一个重要的市场机会。

Severe mucosal Candida albicans is a major cause of morbidity and mortality in immunosuppressed individuals and less toxic therapeutic agents are needed. Our collaborator, Dr. Luciano Polonelli has prepared a number of yeast killer toxin (KT) anti-idiotype antibodies (KT-ID Mab) that mimic the cytotoxic activity versus Candida and Pneumocystis of the native killer toxin. Native KT Cannot be used because it is unstable, immunogenic and has much reduced activity at neutral pH. The KT-ID Mab applied topically in rodent models was effective versus both vaginal candidiasis and pulmonary P. carinii infections. The plant molecular biology unit of Panorama Research Inc. (PRI) has pioneered proprietary methods for the production of secretory lgA antibodies in transgenic plants. SigA plantibodies are the preferred form of antibody therapy for mucosal use. The overall goal of the present project is to prepare an SIgA form of this anti-ID as an economical, stable, therapeutic for C. albicans infection. In phase I we will construct secretory IgA plantibody expression cassettes using the bioactive scFv having demonstrated candidacidal activity. These will be used to transform tobacco by particle bombardment and plants expressing assembled SIgA will be selected. Next we will demonstrate cytotoxic activity of the purified anti-ID SIgA plantibody using in vitro candidacidal assays. Successful completion of this project will demonstrate a general proprietary method to combat difficult mucosal pathogens. PROPOSED COMMERCIAL APPLICATIONS: Severe mucosal candidiasis infections are a major problem. A novel therapeutic represents a significant market opportunity.