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200万种疾病和23，000 在美国，每年的死亡是由抗微生物剂抗性细菌引起的。革兰氏阴性（G-） 病原体尤其令人担忧，因为它们造成了大约99，000人死亡和200亿美元的医疗保健费用， 年更令人担忧的是，由于快速的感染，G-感染的治疗选择变得越来越有限。 对现有和新批准的抗菌药物的多药耐药性（MDR）的出现，突出了 需要替代策略来预防MDR G-感染。因此，利用免疫学的试剂 预防高危人群感染药物敏感和MDR菌株的机制将 在满足这一需求方面具有独特的优势。创新的Cloudbreak™抗体药物 Cidara Therapeutics开发的缀合物（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。与成功的癌症双特异性剂类似，ADC结合保守的 通过靶向部分（TM）靶向病原体，同时接合免疫系统的多个臂， 系统通过效应部分（EM）。TM由二聚体肽组成，所述二聚体肽紧密结合至 脂多糖（LPS），并赋予广谱G-覆盖与有效的内在抗微生物活性。 EM是人IgG 1 Fc，其共同激活补体依赖性细胞毒性（CDC），抗体 （Ab）依赖性细胞介导的细胞毒性（ADCC）和Ab依赖性细胞吞噬作用（ADCP），以清除MDR G-通过宿主细胞上的Fcγ受体识别来自宿主的病原体。这种创新的方法， 具有固有细胞杀伤的有效细胞靶向通过更有效地呈现免疫应答来催化强有力的免疫应答。 病原体对免疫成分的清除。CTC-026是我们的主要ADC候选产品， 作为免疫预防剂具有非常有前途的特性：广谱抗菌活性， 内在和免疫驱动，啮齿类动物中的急性安全性，大肠杆菌脓毒症小鼠模型中的体内有效性 和鲍曼不动杆菌肺炎，以及在小鼠中的67小时血浆半衰期。进一步优化效价 和光谱和深入评价的药理学和毒理学性质的这种铅提出 在本申请中，本提案的总体目标是确定合格的潜在客户开发候选人 在第3年，并在第5年结束时获得研究性新药（IND）候选药物，符合以下标准：1） IV制剂的可接受稳定性和溶解度，2）对以下临床分离株（包括MDR）的MIC 90 ≤1 µM 克雷伯菌属、不动杆菌属、假单胞菌属和大肠埃希菌属。3）对MCR-1、MCR-2和其他粘菌素的MIC 90 ≤1 µM- 耐药G-临床分离株，4）在时间窗内对MDR G-感染的稳健体内预防功效 感染前48- 72小时，5）PK/PD参数，以支持每周一次或更好的人体给药，6）NOAEL 在大鼠和食蟹猴的GLP毒理学研究中， 剂量，和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.