Novel bi-specific immunoprophylactics against multi-drug resistant Gram-negativebacterial infections

针对多重耐药革兰氏阴性细菌感染的新型双特异性免疫预防剂

• 批准号: 10380759
• 负责人: David S Perlin
• 金额: $ 107.68万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-22 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380759
• 关键词: Acinetobacter; Acinetobacter baumannii; Acinetobacter baumannii pneumonia; Acute; Address; Adverse effects; Anti-Bacterial Agents; Antibodies; Antibody-drug conjugates; Antimicrobial Resistance; Bacteria; Binding; Cardiovascular system; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Colistin; Collaborations; Colony-forming units; Complement-Dependent Cytotoxicity; Development; Dose; Dose Fractionation; Drug Kinetics; Drug resistance; Enterobacter; Escherichia coli; Evaluation; Fc domain; Formulation; Goals; Half-Life; Health Care Costs; Health system; Hour; Human; IgG1; Immune; Immune response; Immune system; Immunologics; In Vitro; Infection; Infection prevention; Investigational Drugs; Kidney; Klebsiella; Klebsiella pneumoniae; Lead; Life; Lipopolysaccharides; Lung infections; Macaca fascicularis; Malignant Neoplasms; Mediating; Methods; Microbiology; Modeling; Monkeys; Multi-Drug Resistance; Mus; Mutation; New Agents; New Jersey; Peptides; Phagocytosis; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Pharmacology and Toxicology; Plasma; Property; Pseudomonas; Pseudomonas aeruginosa; Public Health; Rattus; Research Institute; Resistance; Rodent; Safety; Sepsis; Septicemia; Solubility; Systemic infection; Therapeutic; Therapeutic Uses; Time; Tissues; Toxicokinetics; Toxicology; United States; Universities; Validation; Whole Blood; Work; antibody-dependent cell cytotoxicity; antimicrobial; antimicrobial drug; arm; bacterial resistance; base; cell killing; clinical efficacy; colistin resistance; dimer; drug candidate; drug metabolism; drug synthesis; experimental study; high risk population; improved; in vivo; innovation; lead series; medical schools; mouse model; neonatal Fc receptor; novel; pathogen; pathogenic bacteria; prevent; programs; prophylactic; public health research; receptor; receptor binding; resistant strain; respiratory; safety study; screening

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.

美国疾病控制与预防中心（CDC）估计，至少有200万人患病，23,000人死亡