MAb Passive Vaccination against Acinetobacter baumannii

针对鲍曼不动杆菌的 MAb 被动疫苗接种

基本信息

批准号：
10634737
负责人：
BRAD J SPELLBERG
金额：
$ 78.8万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-25 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10634737
关键词：
Acinetobacter baumannii Adoption Amino Acid Sequence Anti-Bacterial Agents Antibiotic susceptibility Antibiotics Antibodies Bacteremia Bacteria Binding Biological Assay Blood CLIA certified Cells Cessation of life China Clinical Clinical Microbiology Clinical Trials Collection Death Rate Developed Countries Development Dose Drug resistance Ensure Europe Evaluation Exposure to Future Goals Grant HL60 Health Care Costs Human Immune system In Vitro Individual Infection Inflammatory Response International Laboratories Lead Leukocytes Lung infections Macrophage Manuals Mediating Modeling Multivariate Analysis Mus Outcome Patients Phase Phase I Clinical Trials Plasma Predisposition Progress Reports Proteins Regimen Reporting Resistance Sepsis Serum South America Southeastern Asia Surrogate Markers Surveys Taiwan Testing Therapeutic Therapeutic Monoclonal Antibodies Time Toxic effect Translations Vaccination Vaccines Work bacterial resistance capsule clinical development cytokine efficacy evaluation high throughput screening improved outcome in vivo in vivo evaluation infection rate lead candidate manufacturing cost news novel operation pathogen pneumonia model preclinical development prevent rapid test research clinical testing statistics synergism uptake virtual

项目摘要

PROJECT SUMMARY/ABSTRACT In contrast to other resistant bacteria, virtually no antibiotics are in the pipeline to deal with XDR A. baumannii. There is a critical need for new strategies to prevent and treat these infections. We spent the first grant period raising MAbs to A. baumannii capsule, and have now identified 4 anti-capsular MAbs (2 of which were used to generate a bi-specific MAb, leaving us with 3 MAb molecules) that collectively bind to 80-90% of US clinical isolates and protect mice from lethal infection. These 3 lead candidates are all highly potent, achieving 100% protection in bacteremia models at single doses of ≤ 50 µg. They are also protective in pneumonia models of infection, and synergize with antibacterials. Furthermore, the bi-specific MAb has increased potency compared to each of its individual MAbs, and retains binding for all target strains, and efficacy in vivo. This lead three- MAb therapeutic has begun translation into full GMP and toxicity, planning for a future Phase I clinical trial. Our goals for the renewal are to enhance feasibility of clinical development and deployment of the MAbs by closing any coverage gaps against international strains, defining surrogate efficacy markers, and validating key assays to support clinical trials and future clinical deployment. We have obtained a new global strain collection, and entered into key partnerships to further these aims, including experts at multi-valent MAb synthesis, clinical microbiology laboratory operations, and statistics. Our Aims are to: Specific Aim 1: Define and optimize strain coverage and surrogate efficacy markers for international clinical strains of A. baumannii. We have collected 50 strains each from Taiwan, Southeast Asia, China, Europe, and South America. We will survey our 3 MAbs against all acquired strains, assessing flow binding and macrophage uptake, and will assess efficacy in our IV bacteremia model for representative strains. We will raise news MAbs as needed to close international strain coverage gaps. Specific Aim 2: Validate bioassays to enable clinical trials of the MAbs, including potency and human surrogate efficacy markers. We will validate LC-MS/MS for the specific amino acid sequences of our variable regions to quantify our MAbs when spiked into human blood, distinct from background antibodies. We will adapt our well-established HL-60 assays to quantify opsonic activity of MAb in human plasma. Finally, we will use multiplex Luminex assays to quantify cytokine modulation of fresh human leukocytes. Specific Aim 3: Optimize a rapid in vitro binding assay as a “susceptibility testing”-equivalent to support clinical trials and deployment of the MAbs. We will validate rapid, high throughput flow binding assays to correlate with protection in mice as a “susceptibility-test equivalent”. Novel solutions for A. baumannii infections are a critical unmet need. We have developed a promising MAb regimen that improves outcomes during blood and lung infection in mice. We will define global strain coverage, close any identified gaps, and develop bioassays to support clinical testing of the MAbs.

项目概要/摘要与其他耐药细菌相比，实际上没有任何抗生素正在研发中来应对 XDR 鲍曼不动杆菌。我们迫切需要新的策略来预防和治疗这些感染。将单克隆抗体转化为鲍曼不动杆菌胶囊，现已鉴定出 4 种抗荚膜单克隆抗体（其中 2 种用于产生双特异性 MAb，使我们只剩下 3 个 MAb 分子），它们共同结合 80-90% 的美国临床药物隔离并保护小鼠免受致命感染这 3 种主要候选药物均非常有效，达到 100%。单剂量≤ 50 µg 对菌血症模型具有保护作用它们对肺炎模型也具有保护作用。此外，与抗菌药物相比，双特异性 MAb 的效力有所增强。与其每个单独的 MAb 结合，并保留与所有目标菌株的结合以及体内功效，这导致了三点。 MAb 疗法已开始转化为完整的 GMP 和毒性，并计划未来的 I 期临床试验。我们更新的目标是提高临床开发和部署的可行性通过缩小针对国际菌株的覆盖差距、定义替代功效标记物以及验证关键测定以支持临床试验和未来的临床部署我们已经获得了新的全球性。菌株收集，并建立了重要的合作伙伴关系以进一步实现这些目标，其中包括多价 MAb 专家合成、临床微生物学实验室操作和统计我们的目标是：具体目标 1：定义和优化国际菌株覆盖率和替代功效标记我们从台湾、东南亚、中国各收集了 50 株鲍曼不动杆菌的临床菌株。我们将针对所有获得的菌株调查我们的 3 种单克隆抗体，评估流结合。和巨噬细胞的摄取，并将评估我们的 IV 菌血症模型中代表性菌株的功效。将根据需要发布新的单克隆抗体，以缩小国际菌株覆盖范围的差距。具体目标 2：验证生物测定，以实现单克隆抗体的临床试验，包括效力和人体试验我们将验证 LC-MS/MS 的特定氨基酸序列。与背景抗体不同，当我们的单克隆抗体掺入人体血液时，可以使用可变区域来对其进行定量。将采用我们完善的 HL-60 测定来量化人血浆中 MAb 的调理活性。将使用多重 Luminex 测定来量化新鲜人类白细胞的细胞因子调节。具体目标 3：优化快速体外结合测定作为“敏感性测试”——相当于支持单克隆抗体的临床试验和部署，我们将验证快速、高通量的流结合。与小鼠保护相关的测定作为“敏感性测试等效物”。鲍曼不动杆菌感染的新解决方案是一个未满足的关键需求，我们开发了一种有前途的单克隆抗体。改善小鼠血液和肺部感染结果的方案我们将定义全局应变。覆盖范围，弥补任何已发现的差距，并开发生物测定法以支持单克隆抗体的临床测试。

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A nutrient-limited screen unmasks rifabutin hyperactivity for extensively drug-resistant Acinetobacter baumannii.

营养限制筛查揭示了利福布丁对广泛耐药的鲍曼不动杆菌的过度活性。

DOI：
发表时间：
2020-09
期刊：
影响因子：
28.3
作者：
Luna, Brian;Trebosc, Vincent;Lee, Bosul;Bakowski, Malina;Ulhaq, Amber;Yan, Jun;Lu, Peggy;Cheng, Jiaqi;Nielsen, Travis;Lim, Juhyeon;Ketphan, Warisa;Eoh, Hyungjin;McNamara, Case;Skandalis, Nicholas;She, Rosemary;Kemmer, Christian;Lociuro, Se
通讯作者：
Lociuro, Se

Duration of Antibiotic Therapy: Shorter Is Better.

抗生素治疗的持续时间：越短越好。

DOI：
发表时间：
2019
期刊：
影响因子：
39.2
作者：
Spellberg, Brad;Rice, Louis B
通讯作者：
Rice, Louis B

The Maturing Antibiotic Mantra: "Shorter Is Still Better".

成熟的抗生素口头禅：“越短越好”。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Spellberg; Brad
通讯作者：
Brad

In Vitro Activity of Rifabutin and Rifampin against Antibiotic-Resistant Acinetobacter baumannii, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae.

利福布丁和利福平对抗生素耐药鲍曼不动杆菌、大肠杆菌、金黄色葡萄球菌、铜绿假单胞菌和肺炎克雷伯菌的体外活性。

DOI：
发表时间：
2021-12-22
期刊：
影响因子：
4.8
作者：
Lee, Bosul;Yan, Jun;Ulhaq, Amber;Miller, Sarah;Seo, Wonjae;Lu, Peggy;She, Rosemary;Spellberg, Brad;Luna, Brian
通讯作者：
Luna, Brian

Oral Is the New IV. Challenging Decades of Blood and Bone Infection Dogma: A Systematic Review.

口头是新的 IV。

DOI：
发表时间：
2022-03
期刊：
影响因子：
0
作者：
Wald;Holtom, Paul D;Phillips, Matthew C;Centor, Robert M;Lee, Rachael A;Baden, Rachel;Spellberg, Brad
通讯作者：
Spellberg, Brad