ANTI-C. DIFFICILE HUMAN MONOCLONALS FOR IMMUNOTHERAPY

描述(申请人提供)：艰难梭菌相关性疾病(CDAD)是医院和疗养院患者发病率的重要原因，并日益被认为是死亡的重要原因。本项目的目的是制备用于预防和治疗CDAD的人源单抗。利用含有人免疫球蛋白基因座的转基因小鼠，已经产生了针对艰难梭菌的两种毒素的人源单抗。在第一个特定目标中，将表征单抗在体外的毒素中和活性，以及它们的特异性和抗原结合动力学。将选择具有最理想的毒素结合动力学的最有效的中和单抗在中空纤维系统中生产，以产生足够的量用于体内实验。第二个具体目标是在艰难梭菌感染的仓鼠模型中评估这些单抗。口服单抗将测试对CDAD的预防和治疗效果，并将选择最有效的单抗用于临床开发。

DESCRIPTION (provided by applicant): Clostridium difficile associated disease (CDAD) is an important cause of morbidity in hospital and nursing home patients, and is being increasingly recognized as an important cause of mortality. The objective of this project is to produce human monoclonal antibodies (Mabs) for the prevention and therapy of CDAD. Human Mabs have been generated against the two toxins of C. difficile using transgenic mice containing human immunoglobulin gene loci. In the first specific aim, Mabs will be characterized for their toxin neutralizing activity in vitro, as well as their specificity and antigen binding kinetics. The most potent neutralizing Mabs with the most desirable toxin-binding kinetics will be selected for production in a hollow fiber system to generate sufficient quantities for in vivo experiments. The second specific aim will evaluate these Mabs in a hamster model of C. difficile infection. Oral administration of the Mabs will be tested for prophylactic and therapeutic efficacy against CDAD, and the most effective Mabs will be chosen for clinical development.