FimH-Targeting Antibody-Recruiting Molecules as Novel Drugs for Preventing Complicated Urinary Tract Infections

FimH 靶向抗体招募分子作为预防复杂性尿路感染的新药

• 批准号: 10603693
• 负责人: Michael Einer Hibbing
• 金额: $ 30万
• 依托单位: FIMBRION THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10603693
• 关键词: Acute; Adhesives; Affinity; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antibodies; Antimicrobial Resistance; Bacteria; Bacterial Adhesins; Benchmarking; Binding; Biological Availability; Bladder; Blood; Case Fatality Rates; Catheters; Cells; Clinical Treatment; Clinical Trials; Collaborations; Complex; Data; Development; Dose; Drug Design; Drug Kinetics; Enterobacteriaceae; Epithelium; Extended-spectrum β-lactamase; Generations; Goals; Gram-Negative Bacterial Infections; Half-Life; Health; Human; Immune; Immune system; Immunize; Impairment; Implant; In Vitro; Infection; Infective cystitis; Intensive Care; Invaded; Klebsiella pneumoniae; Lead; Libraries; Long-Term Care; Mannose; Mannose Binding Lectin; Mannosides; Mediating; Microbial Biofilms; Mission; Modeling; Monoclonal Antibodies; Multi-Drug Resistance; Mus; Oral; Outcome; Parents; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase Ib Clinical Trial; Pilum; Prevention; Prevention therapy; Property; Prophylactic treatment; Proteins; Public Health; Recurrence; Research; Rhamnose; Risk; Severities; Small Business Innovation Research Grant; Surface; Testing; Therapeutic; Urinary Catheterization; Urinary tract infection; Urination; Urine; Uropathogen; Uropathogenic E. coli; Virulence Factors; antagonist; antimicrobial; carbapenem-resistant Enterobacteriaceae; clinical candidate; combat; commercial application; comorbidity; design; follow-up; gut microbiome; health care settings; immune function; in vitro Assay; in vivo; innovation; lead optimization; lead series; mouse model; nanomolar; novel; novel therapeutics; pathogen; pathogenic bacteria; phase 1 study; preclinical development; preclinical study; prevent; programs; prototype; recruit; renal scarring; small molecule; standard of care; subcutaneous; success; urinary; urinary bladder epithelium

1 ABSTRACT. Urinary tract infections (UTI) are extremely common world-wide, and can lead to serious 2 complications, including renal scarring and urosepsis. Standard-of-care treatments rely on antibiotics: empiric 3 treatment for uncomplicated UTI (uUTI), broad-spectrum for complicated UTI (cUTI), and long-term prophylaxis 4 for recurrent UTI (rUTI). This constant antibiotic exposure not only disrupts the gut microbiome but drives 5 antimicrobial resistance among uropathogenic Escherichia coli (UPEC) and Klebsiella pneumoniae (Kp), the 6 predominant causative agents of UTI. The global spread of multidrug-resistant uropathogens, such as those 7 caused by extended spectrum b-lactamase (ESBL)-producing and carbapenem-resistant Enterobacteriaceae 8 (CRE), has been designated by the CDC as “serious” and “urgent” public health threats, respectively. Therefore, 9 new strategies to combat multidrug resistance are desperately needed. One such approach is to target and 10 inhibit the function a key virulence factor of UPEC and Kp, the FimH adhesin. FimH is a surface-exposed, 11 mannose-binding protein that facilitates bacterial binding to the host urinary bladder epithelium, and its function 12 is essential for the establishment and persistence of a UTI. Using this anti-adhesive strategy, a small molecule 13 mannoside FimH antagonist was developed by Fimbrion and GlaxoSmithKline and is currently in Phase 1b 14 clinical trials for the treatment of uUTI. As a follow-up to this collaboration, we began exploring the next 15 generation of FimH antagonists that target the more difficult-to-treat cUTI, by additionally recruiting antibodies 16 from the host immune system. Known as FimH antagonist antibody recruiting molecules (FimH-ARMs), these 17 mannoside-based therapeutics have nanomolar affinity for the FimH target and our early protype FimH-ARM has 18 shown enhanced ability to reduce the severity of acute bladder infection in a mouse model of uUTI. We 19 hypothesize that in addition to antagonism of FimH function, FimH-ARMs will provide additional mechanisms of 20 action (MoAs) through engagement of the immune system and extended pharmacokinetics (PK), resulting in 21 superior efficacy over conventional mannosides in cUTI. The main goals of this proposal are: (1) to generate a 22 highly potent lead series of FimH-ARMs that will recruit naturally occurring human antibodies to uropathogenic 23 bacteria and (2) demonstrate in vivo efficacy in a model of cUTI. To accomplish these goals, we will (i) expand 24 the FimH-ARM library to identify potent lead compounds with optimized mouse PK profiles, and (ii) test the in 25 vivo efficacy of lead FimH-ARMs in a mouse cUTI model and (iii) Select our advanced lead FimH-ARM and 26 establish the spectrum of activity, MoA, and PK benchmarks for late lead optimization in Phase II. Success will 27 be defined as: identification of an advanced lead FimH-ARM, that shows in vivo efficacy superior to its parent 28 small molecule FimH antagonist and non-inferiority to a standard-of-care antibiotic and demonstrates additional 29 immune system MoAs beyond FimH antagonism. These studies will facilitate the early preclinical development 30 of a novel, antibiotic-sparing therapeutic, for preventing cUTI caused by FimH-expressing uropathogens.

1摘要。尿路感染（UTI）在全球范围内非常普遍，可能导致严重 2个并发症，包括肾脏疤痕和尿素。护理标准治疗依赖抗生素：经验性 3对简单UTI（UUTI），复杂UTI（CUTI）和长期预防的宽光谱治疗 4对于复发性UTI（RUTI）。这种恒定的抗生素暴露不仅破坏了肠道微生物组，而且驱动 5尿道病大肠杆菌（UPEC）和肺炎克雷伯氏菌（KP）中的抗菌素耐药性 6 UTI的主要因果剂。抗多药的尿道病的全球传播，例如 7由扩展的频谱B-内酰胺酶（ESBL）引起的产生和抗碳青霉烯的肠杆菌科引起 8（CRE）被疾病预防控制中心指定为“严重”和“紧急”公共卫生威胁。所以， 迫切需要9种对抗多药抵抗的新策略。一种这样的方法是针对目标和 10抑制功能是UPEC和KP（FIMH粘附素）的关键病毒因子。 FIMH是一个表面暴露的 11甘露糖结合蛋白，促进细菌与宿主泌尿膀胱上皮的结合及其功能 12对于UTI的建立和持久性至关重要。使用这种抗粘合剂策略，一个小分子 13 mannoside fimh拮抗剂是由fimbrion和glaxosmithkline开发的，目前处于1B期 14个治疗UUTI的临床试验。作为这项合作的后续，我们开始探索下一个 15通过募集抗体的靶向更难治疗的cuti的FIMH拮抗剂 16来自宿主免疫系统。这些被称为FIMH拮抗剂抗体募集分子（FIMH-arrs），这些 17基于甘露糖苷的治疗对FIMH靶标具有纳摩尔亲和力，我们的早期原型FIMH臂具有 18显示了在UUTI小鼠模型中降低急性膀胱感染严重程度的增强能力。我们 19假设，除了FIMH功能的拮抗作用外，FIMH臂还将提供其他机制 20通过接合免疫系统和扩展药代动力学（PK）的20行动（MOAS），导致 21超过Cuti中常规甘露糖苷的效率高。该提案的主要目标是：（1）生成一个 22个高潜在的铅系列FIMH臂，这些系列将募集自然发生的人类抗体抗体 23细菌和（2）在CUTI模型中表现出体内效率。为了实现这些目标，我们将（i）扩展 24 FIMH-ARM库鉴定具有优化鼠标PK轮廓的潜在铅化合物，以及（ii）测试IN 25小鼠Cuti模型中铅FIMH臂的体内效率，（iii）选择我们的先进铅fimh-arr和 26建立活性，MOA和PK基准的频谱，以在II阶段中延迟铅优化。成功将 27被定义为：识别高级铅fimh-arm，显示出优于其父母的体内效率 28小分子FIMH拮抗剂和对护理标准抗生素的非效率，并证明了额外的 29免疫系统MOA超出FIMH拮抗作用。这些研究将促进早期临床前发展 30种新型抗生素疗法，用于预防由表达FIMH的尿道疾病引起的CUTI。