Novel bi-specific immunoprophylactics against multi-drug resistant Gram-negative bacterial infections

疾病控制和预防中心(CDC)估计，至少有200万人患病，23000人 在美国，每年的死亡都是由抗菌素耐药性细菌造成的。革兰氏阴性(G-) 病原体尤其令人担忧，因为它们每年造成约99,000人死亡和200亿美元的医疗费用 年。更令人担忧的是，G感染的治疗选择越来越有限，因为 对现有和新批准的抗菌剂出现多药耐药(MDR)，突出了 需要采取替代战略来预防耐多药G-感染。因此，一种利用免疫学 预防药物敏感和耐多药菌株感染高危人群的机制将 在满足这一需求方面拥有独特的优势。创新的CloudBreak™抗体药物 Cidara Treeutics开发的共轭化合物(ADC)平台使用了一种全新的基于免疫的 预防和治疗G感染的方法。类似于成功的癌症双特异性药物，ADC结合保守 通过靶向部分(TM)靶向病原体，同时接触免疫的多个手臂 系统通过效应器部分(EM)。TM是由一种二聚体多肽组成的，它与 脂多糖(LPS)，并赋予广谱G-覆盖，具有强大的内在抗菌活性。 EM是一种人IgG1Fc，它能集体激活补体依赖性细胞毒(CDC)抗体 (AB)依赖细胞介导的细胞毒性(ADCC)和抗体依赖的细胞吞噬(ADCP)以清除MDR 来自宿主的G-病原体，通过宿主细胞上的Fcγ受体识别。 高效的细胞靶向与固有的细胞杀伤通过更有效地呈递 病原体对免疫成分进行清除。CTC-026是我们的主要ADC候选者，并已展示 作为免疫预防药物的极具前景的特性：广谱抗菌活性，即 本征和免疫驱动，对啮齿动物的急性安全性，在小鼠模型中对大肠杆菌败血症的体内疗效 鲍曼不动杆菌肺炎，以及小鼠67小时的血浆半衰期。进一步优化效能 并对该铅的药理和毒理性质进行了波谱和深入评价。 在此应用程序中。这项提议的首要目标是确定一位合格的领导发展候选人 在第三年，并在第五年年底之前成为研究用新药(IND)候选药物，满足以下标准：1) IV制剂的可接受的稳定性和溶解性，2)MIC90≤1µM对临床分离株(包括mdr)的抗药性 克雷伯氏菌、不动杆菌、假单胞菌和大肠埃希菌，3)MIC90对Mcr-1、Mcr-2和其他粘菌素的≤为1µM。 耐药G-临床分离株，4)在一个时间窗口内对MDR G-感染的体内强大预防效果 感染前48-72小时，5)PK/PD参数以支持人类每周一次或更好的剂量，6)无AEL 在对大鼠和食蟹猴的GLP毒理学研究中，至少是目标临床试验的五倍 剂量，以及7)GMP产品的可扩展合成。

The Centers for Disease Control and Prevention (CDC) estimates that at least two million illnesses and 23,000 deaths annually are caused by antimicrobial-resistant bacteria in the United States. The Gram-negative (G-) pathogens are of particular concern, as they account for roughly 99,000 deaths and $20B in health care costs a year. More alarming, treatment options for G- infections have become increasingly limited due to rapid emergence of multi-drug resistance (MDR) to existing and newly approved antimicrobial agents, highlighting the need for alternative strategies to prevent MDR G- infections. Thus, an agent that leverages immunological mechanisms to prevent infection in high risk populations from drug susceptible and MDR strains would possess a unique advantage in addressing this need. The innovative Cloudbreak™ Antibody Drug Conjugates (ADCs) platform, developed at Cidara Therapeutics, uses a fundamentally new immune-based approach to prevent and treat G- infections. Similar to successful cancer bispecific agents, ADCs bind conserved targets on pathogens via a Targeting Moiety (TM) while simultaneously engaging multiple arms of the immune system via an Effector Moiety (EM). The TM is comprised of a dimeric peptide that binds tightly to lipopolysaccharide (LPS) and confers broad spectrum G- coverage with potent intrinsic antimicrobial activity. The EM is a human IgG1 Fc, which collectively activates complement dependent cytotoxicity (CDC), antibody (Ab)-dependent cell-mediated cytotoxicity (ADCC), and Ab-dependent cell phagocytosis (ADCP) to clear MDR G- pathogens from the host, via recognition by Fcγ receptors on host cells.!This innovative approach involving efficient cell targeting with inherent cell killing catalyzes a robust immune response by more effectively presenting the pathogen to immune components for clearance. CTC-026 is our lead ADC candidate and has demonstrated highly promising properties as an immunoprophylactic agent: broad spectrum antibacterial activity that is both intrinsic and immune-driven, acute safety in rodents, in vivo efficacy in mouse models of Escherichia coli sepsis and Acinetobacter baumannii pneumonia, and a 67 hour plasma half-life in mice. Further optimization of potency and spectrum and in-depth evaluation of pharmacological and toxicological properties of this lead are proposed in this application. The overarching goal of this proposal is to identify a qualified lead development candidate in Year 3 and an Investigational new drug (IND) candidate by the end of Year 5, that meets these criteria: 1) acceptable stability and solubility for IV formulation, 2) MIC90s ≤1 µM against clinical isolates (including MDR) of Klebsiella, Acinetobacter, Pseudomonas and E. coli, 3) MIC90s ≤1 µM against MCR-1, MCR-2 and other colistin- resistant G- clinical isolates, 4) robust in vivo prophylactic efficacy against MDR G- infections in a time window 48-72h prior to infection, 5) PK/PD parameters to support once weekly or better dosing in humans, 6) a NOAEL in GLP toxicology studies in rats and Cynomolgus monkeys at least fivefold higher than the targeted clinical dose, and 7) a scalable synthesis to GMP product.