Therapeutic Antibodies for Biofilm Infections

摘要 美国疾病控制与预防中心估计，65%-80%的临床上重要的耐药细菌感染是由于 与生物膜形成相关的病原体的生理状态的变化有关。TRL1068是一种高亲和力(100 PM)通过提取关键的细菌支架来破坏生物膜的天然人类单抗(MAb) 蛋白。该表位在广泛的革兰氏阳性的靶蛋白同源物中高度保守。 和革兰氏阴性菌，包括所有ESKAPE病原体。释放的细菌重新对 抗生素。金黄色葡萄球菌和几克金黄色葡萄球菌的生物被膜破坏已在体外得到证实 阴性菌：铜绿假单胞菌、鲍曼不动杆菌、肺炎克雷伯菌。在体内， TRL1068与抗生素联合使用与单独使用抗生素相比，显示出统计上显著的疗效 两种动物模型(小鼠植入物感染和感染性心内膜炎)中的耐甲氧西林金黄色葡萄球菌(MRSA) 在软组织感染的小鼠模型中，对耐药鲍曼不动杆菌的临床分离株进行了研究。 临床毒性风险很低，因为该表位不存在于人类蛋白质组中，而mAb是从 健康的人类捐赠者。与FDA成功地举行了IND前会议，并促进了IND的开发 活动由一个经验丰富的团队进行，部分资金来自NIAID提供的第二阶段SBIR赠款。少校 SBIR基金的目标是开发一个主细胞库(MCB)，以商业用途生产TRL1068 随着产品特异性检测方法的发展，检测水平也在不断提高。混合CHO细胞转染期的表达 在亚克隆和优化上游和下游加工之前在预期范围内。这个 剩余的SBIR工作失败风险很低，将于2017年第三季度完成。我们现在寻求CRP资金以 完成支持IND的临床前开发，包括毒理学研究，额外的动物疗效 研究和制造足够的材料，用于第一阶段和第二阶段的人体临床试验。有了CRP资金 预计将在SBIR第二阶段资金结束后不久开始，我们预计IND将在30个月内提交 在收到CRP资金后。SBIR或CRP资金将不用于实际的临床试验费用。

Abstract The CDC estimates that 65-80% of clinically significant drug resistant bacterial infections are drug refractory due to a change in physiological state of pathogens associated with biofilm formation. TRL1068 is a high affinity (100 pM) native human monoclonal antibody (mAb) that disrupts biofilms by extracting a key bacterial scaffolding protein. The epitope is highly conserved in the target protein homologs across a broad spectrum of gram positive and gram negative bacteria, including all ESKAPE pathogens. The released bacteria regain sensitivity to antibiotics. Biofilm disruption has been demonstrated in vitro for Staphylococcus aureus and for several gram negative species: Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae. In vivo, TRL1068 in combination with an antibiotic vs. antibiotic alone has shown statistically significant efficacy against methicillin resistant S. aureus (MRSA) in two animal models (infected implants in mice and infective endocarditis in rats) and against a drug resistant clinical isolate of A. baumannii in a mouse model of soft tissue infection. Clinical toxicity risk is low, as the epitope is not present in the human proteome and the mAb was cloned from a healthy human donor. A successful pre-IND meeting with the FDA has been held and IND-enabling development activities are underway by an experienced team funded in part by a Phase II SBIR grant from NIAID. The major goal of the SBIR funding is to develop a Master Cell Bank (MCB) producing TRL1068 at commercially useful levels along with development of product specific assays. Expression at the pooled CHO cell transfection stage is within the expected range prior to subcloning and optimization of upstream and downstream processing. The remaining SBIR work has low risk of failure and will be completed in Q3 2017. We now seek CRP funding to complete the IND-enabling preclinical development including toxicology studies, additional animal efficacy studies, and manufacturing of sufficient material for Phase 1 and Phase 2 human clinical trials. With CRP funding projected to start shortly after the end of the SBIR Phase II funding, we anticipate IND filing within 30 months after receipt of CRP funding. No SBIR or CRP funding will be used for actual clinical trial expenses.