Novel anti-bacterial therapy for gram negative pneumonia

描述（由申请人提供）：尽管进行了积极的抗生素治疗， 和支持性治疗，革兰氏阴性肺炎仍然是死亡的主要原因， 延长住院时间。为了满足这一未满足的需求，Inotek正在开发一种 一种基于抗体的策略，靶向鞭毛蛋白，一种关键的毒力因子， 革兰氏阴性病原体。鞭毛是有效的细菌 上皮细胞浸润。此外，鞭毛蛋白是一种非常有效的触发剂， NF-κ B活化和促炎基因表达，因此可能 导致宿主对局部感染的过度有害反应。 针对N-末端的主动和被动免疫策略 鞭毛蛋白结构域降低沙雷氏菌属LD 90 -100小鼠模型的死亡率 粘质虫引起的急性肺炎小于10%。这种程度的 保护作用与体内细菌菌落总数减少90%有关 肺，肺中性粒细胞浸润减少95%， 菌血症发生率降低10%。因为N端是 高度保守的免疫反应是交叉保护性的， 革兰氏阴性病原体谱。SBIR第一阶段的中心目标 是获得抗N-末端鞭毛蛋白mAb 在体内对广泛的致命感染有保护作用。我们将测试 14种专有鼠mAb在小鼠模型中的体内保护作用 急性革兰阴性菌肺炎 接种E.线圈具体结果变量包括：1） 药效学特征; 2）治疗机会窗口;和3）谱 对铜绿假单胞菌、粘质沙雷氏菌和 阴沟肠杆菌在后续的II期SBIR中，我们将使用肽 对应于在阶段I中鉴定的前导表位，以产生 人类单克隆抗体。我们将推进领先的单克隆抗体技术， 通过1）优化体外产率和纯度，2）表征 体内半衰期，和3）在两个实验中进行安全性和耐受性研究 物种这些里程碑将为IND提交提供基础， 人类抗鞭毛蛋白广谱mAb的首次临床试验。 拟定商业应用： 由于没有安全有效的市售抗炎药 对于革兰氏阴性肺炎的持续治疗， 未来的市场规模和趋势。我们预计，根据住院人数 严重肺炎患者，市场超过败血症。因此 国内市场非常保守的估计可能是200 -400万美元， 一年。

DESCRIPTION (provided by applicant):In spite of aggressive antibiotic therapy and supportive care, gram negative pneumonia remains a major cause of death and prolonged hospitalization. To address this unmet need, Inotek is developing an antibody-based strategy that targets flagellin, a critical virulence factor of motile gram negative pathogens. Flagella is required for effective bacterial invasion of epithelium. Moreover, flagellin is a highly potent trigger of NF-kappa B activation and pro-inflammatory gene expression, and thus may contribute to the excessive deleterious host response to regional infection. Both active and passive immunization strategies that target the N-terminal domain of flagellin reduce mortality in LD9O-100 murine models of Serratia marcescens induced acute pneumonia to less than 10 percent. This level of protection is associated with a 90 percent reduction in bacterial cfu in the lung, a 95 percent decrease in pulmonary neutrophil infiltration, and a 50 percent reduction in the incidence of bacteremia. Because the N-terminus is highly conserved, immune responses are cross-protective against a broad spectrum of gram negative pathogens. The central objective of the Phase I SBIR is to obtain proof of principle that anti-N-terminal flagellin mAb's are protective in vivo against a broad spectra of lethal infection.We will test the in vivo protective action of 14 proprietary murine mAb's in a murine model of acute gram negative bacterial pneumonia produced by intratracheal bacterial inoculation of E. coil. Specific outcome variables will include: 1) Pharmacodynamic profile; 2) Therapeutic window of opportunity; and 3) Spectrum of activity against Pseudomonas aeruginosa, Serratia marcescens, and Enterobacter cloacae. In a follow-on Phase II SBIR, we will use the peptide corresponding to the lead epitopes identified in Phase I in order to produce a human mAb.We will then advance the lead mAb technology towards commercialization by 1) optimizing in vitro yield and purity, 2) characterizing in vivo half-life, and 3) performing safety and tolerance studies in two species. These milestones will provide a foundation for IND submission and the first clinical trials of a human anti-flagellin broad-spectrum mAb. PROPOSED COMMERCIAL APPLICATION: Since there are no marketed anti-inflammatory agents that are safe and effective for the adjunctive therapy of gram negative pnenmocda, it is difficult to predict the future market size and trend. We anticipate, based upon the numbers of hospitalized patients with severe pneumonia, that the market exceeds that for sepsis. Thus, a very conservative estimate of the domestic market may be $200-400 million per annum.