Humanized Monoclonal Antibodies to Treat Acinetobacter Infections

治疗不动杆菌感染的人源化单克隆抗体

• 批准号: 8591208
• 负责人: BRAD J SPELLBERG
• 金额: $ 28.84万
• 依托单位: BIOLOGICAL ANTI-INFECTIVE MEDICINES, LLC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8591208
• 关键词: A Mouse; Acinetobacter Infections; Acinetobacter baumannii; Acute; Adjuvant; Allergic Reaction; Antibiotic Resistance; Antibiotics; Antibodies; Bacteria; Binding; Cell Line; Cell surface; Cessation of life; Clinical; Clinical Research; Clone Cells; Combined Modality Therapy; Competitive Bidding; Data; Development; Diagnosis; Drug resistance; Economics; Epitope Mapping; Epitopes; Evaluation Studies; Excision; Exposure to; Failure; Fc Receptor; Flow Cytometry; Frequencies; Goals; Gram-Negative Bacteria; Harvest; Human; IgG3; Immune; Immunoglobulin Class Switching; In Vitro; Infection; Inflammation; Lead; Marketing; Mediating; Membrane Proteins; Methods; Metric; Monoclonal Antibodies; Mus; Mutation; Pathway interactions; Patients; Phase; Placebos; Preparation; Process; Proteins; Public Health; Reaction; Recombinants; Regimen; Resistance; Risk; Small Business Technology Transfer Research; Surface; Testing; Therapeutic Monoclonal Antibodies; Therapeutic antibodies; Toxicology; Translations; United States; Vaccinated; Vaccines; Vendor; base; clinical toxicology; cost; experience; humanized antibody; humanized monoclonal antibodies; in vitro testing; in vivo; killings; manufacturing process; mouse model; novel; novel therapeutics; pathogen; pre-clinical; prevent; public health relevance; success; treatment effect

DESCRIPTION (provided by applicant): In the last decade, Acinetobacter baumannii has emerged as one of the most highly antibiotic-resistant pathogens in the United States (US) and throughout the world. These infections are increasingly prevalent and highly lethal, killing 50-60% of those infected. Worse, strains of A. baumannii that no known antibiotic will kill have now emerged, and will continue to increase in frequency given the lack of antibiotics in development to treat A. baumannii. Given the tremendous scientific barriers to developing new antibiotics to treat A. baumannii and the economic market failure of antibiotics, new treatments are critically needed for this bacteria. We propose to develop a passive vaccine targeting A. baumannii (i.e., an antibody that can be administered to patients with A. baumannii infection). Our data indicate that antibody-based therapy is a promising strategy to treat A. baumannii infections. We first identified a protein that the bacteria expresses on its surface called OmpA (Outer membrane protein A) that appeared to be a suitable target for a vaccine. We then found that when recombinant OmpA was injected into mice as an active vaccine, and subsequently the vaccinated or control mice were infected with A. baumannii, the vaccine protected mice from otherwise lethal extreme drug resistant (XDR) A. baumannii infection. Next, we discovered that the mechanism of vaccine- mediated efficacy was induction of protective antibodies. We then raised 5 distinct types of monoclonal antibodies (MAbs) against OmpA isolated from A. baumannii. These MAbs enhance opsonophagocytic killing of A. baumannii in vitro and effectively protected mice given a lethal infection with XDR A. baumannii. While these MAbs are a promising new therapy for XDR A. baumannii infections, the feasibility of further clinical development will hinge upon successful humanization of the antibodies. Mouse MAbs cannot be used to treat humans, because humans mount an immune reaction to mouse MAbs that can cause rapid removal of the MAbs (hence lower efficacy), systemic inflammation, severe allergic reactions, and even a risk for death. The humanization process prevents these undesirable effects. We therefore propose to humanize the MAbs while retaining their anti-A. baumannii activity (as verified both in vitro and in vivo) in two AIMS: 1) Humanize 3 lead candidate MAbs, with class switching to human IgG3; 2) Define an optimally effective humanized MAb regimen based on in vitro surface binding and bacterial killing, and in vivo efficacy in a mouse model of A. baumannii infection. A. baumannii infections pose a grave public health threat that urgently demands development of new treatments, but no new antibiotics to treat these infections will likely be available in the coming decade. MAbs hold great promise to treat A. baumannii infections. We propose conservative milestones (feasibility criteria) that are part of a standard, methodical development pathway for our unique MAbs as a novel treatment for such infections. Progression to Phase II depends on humanization of the MAbs without loss of efficacy.

描述(申请人提供)：在过去的十年里，鲍曼不动杆菌已经成为美国和全世界最具高度抗药性的病原体之一。这些感染越来越普遍，致命性很高，导致50%-60%的感染者死亡。更糟糕的是，还没有已知的抗生素可以杀死鲍曼不动杆菌的菌株现已出现，而且由于缺乏治疗鲍曼不动杆菌的抗生素，这种菌株的出现频率还会继续增加。考虑到开发治疗鲍曼不动杆菌的新抗生素的巨大科学障碍，以及抗生素的经济市场失灵，迫切需要新的治疗方法来治疗这种细菌。我们建议开发一种针对鲍曼不动杆菌(即一种可用于感染鲍曼不动杆菌的患者的抗体)的被动疫苗。我们的数据表明，基于抗体的治疗是治疗鲍曼不动杆菌感染的一种有前途的策略。我们首先确定了细菌表面表达的一种名为OmpA(外膜蛋白A)的蛋白质，它似乎是疫苗的合适靶点。然后我们发现，当重组OmpA作为活性疫苗注射到小鼠体内，随后接种疫苗的小鼠或对照小鼠感染鲍曼不动杆菌时，疫苗可以保护小鼠免受其他致命的极端抗药性(XDR)鲍曼不动杆菌的感染。接下来，我们发现疫苗介导的效力机制是诱导保护性抗体。然后，我们制备了5种不同类型的抗鲍曼不动杆菌OmpA的单抗。这些单抗在体外增强了对鲍曼不动杆菌的吞噬细胞杀伤作用，并有效地保护了被XDR鲍曼不动杆菌致死感染的小鼠。虽然这些单抗是治疗XDR鲍曼不动杆菌感染的一种很有前途的新疗法，但进一步临床开发的可行性将取决于抗体的成功人源化。鼠单抗不能用于治疗人类，因为人类对鼠单抗会产生免疫反应，导致单抗迅速清除(因此效率较低)、全身炎症、严重的过敏反应，甚至有死亡的风险。人性化的过程防止了这些不良影响。因此，我们建议将单抗人性化，同时保留其抗A抗体。鲍曼氏杆菌的活性(经体外和体内验证)有两个目的：1)人源化3个主要候选单抗，类别切换为人IgG3；2)定义一种基于体外表面结合和细菌杀灭的最佳人源化单抗方案，以及在鲍曼不动杆菌感染小鼠模型中的体内疗效。鲍曼不动杆菌感染构成了严重的公共卫生威胁，迫切需要开发新的治疗方法，但在接下来的十年里，可能不会有新的抗生素来治疗这些感染。单抗在治疗鲍曼不动杆菌感染方面大有可为。我们提出了保守的里程碑(可行性标准)，这是我们独特的单抗作为治疗此类感染的新方法的标准、系统开发途径的一部分。第二阶段的进展取决于单抗的人性化而不会失去效力。