Receptor Decoy Inhibitor of Anthrax Toxin

炭疽毒素受体诱饵抑制剂

• 批准号: 8206699
• 负责人: MARIANNE MANCHESTER
• 金额: $ 46.42万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8206699
• 关键词: Address; Adverse effects; Affect; Affinity; Animals; Anthrax disease; Antibiotics; Antibodies; Antibody Binding Sites; Antigens; Antitoxins; Bacillus anthracis; Bacillus anthracis spore; Bacteria; Bacterial Typing; Binding; Binding Sites; Bioterrorism; Biothrax; Categories; Cessation of life; Chimeric Proteins; Ciprofloxacin; Collagen Type IV; Complex; Decontamination; Development; Disease; Dissociation; Dominant-Negative Mutation; Drug Kinetics; Edema; Effectiveness; Engineering; FDA approved; Future; Growth; Hour; Immunization; In Vitro; Infection; Intoxication; Laminin; Ligand Binding; Ligands; Mails; Mediating; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Mutation; Pathogenesis; Peptides; Physiological; Population; Prevention strategy; Production; Property; Proteins; Rattus; Reproduction spores; Research; Resistance; Role; Staging; System; Therapeutic; Therapeutic antibodies; Time; Toxin; United States; Vaccines; Virulent; aerosolized; anthrax lethal factor; anthrax toxin; anthrax toxin receptors; cost; edema factor; falls; in vivo; inhibitor/antagonist; killings; neutralizing antibody; next generation; prevent; receptor; receptor binding; research study; therapy development; weapons

The spore-forming bacterium Bacillus anthracis causes anthrax, and is classified as one of six Category A agents considered as major threats as a bioweapon. Because of its pivotal role in disease pathogenesis, a number of strategies to inhibit anthrax toxin are currently under development, including monoclonal antibodybased therapies. However, there is significant concern about the ease with which the bacterium may be engineered to avoid vaccine protection or antitoxin therapy, e.g. by removing antibody-binding sites from the protective antigen (PA) toxin subunit. A next-generation strategy for antitoxin development, one that addresses this limitation, involves the use of a soluble receptor decoy inhibitor (RDI); Presumably PA cannot be engineered to evade cellular receptor recognition and therefore the RDI should be effective even against forms of PA that have been deliberately altered to resist antibody neutralization. We have recently developed an RDI which has many properties desirable in a broadly acting anthrax therapeutic: it binds to the receptor-binding site of PA with an affinity that is on a par with some of the leading therapeutic antibodies (Kd = 0.2nM); it blocks intoxication via both known cellular receptors for anthrax toxin; its dissociation rate from PA is extremely slow (t1/2 complex = 15 hours); it is non-immunogenic; its production is easily scaleable using a bacterial expression system; it can neutralize PA at stoichiometric concentrations and protects rats against toxin killing. This research plan represents a comprehensive strategy for advancing the RDI as a candidate therapy for anthrax. We will characterize and optimize its pharmacokinetic properties by disrupting its interaction with its physiological ligands (collagen IV and laminin), and by exploiting PEGylation and Ig fusion protein approaches. We will also establish if this class of inhibitor is effective at neutralizing antibody-resistant forms of PA, as expected. Moreover, we will establish if this class of inhibitor can prevent disease in mice caused by Sterne spores that express either wild-type or antibody-resistant PA. These experiments will set the stage for future studies aimed at establishing the effectiveness of the RDI in preventing disease caused by highly virulent strains of B. anthracis. We anticipate that the RDI will be a useful adjunct anthrax therapy that could potentially synergize with monoclonal antibodies to treat infections caused by wild-type bacterial strains while at the same time providing a straightforward strategy for dealing with engineered, weaponized bacterial strains.

孢子形成细菌炭疽杆菌导致炭疽病，并被归类为六个A类之一 被视为主要威胁的生物武器。由于其在疾病发病机制中的关键作用， 目前正在开发一些抑制炭疽毒素的策略，包括基于单克隆抗体的 治疗然而，人们非常担心细菌可能很容易被感染。 工程化以避免疫苗保护或抗毒素治疗，例如通过从免疫球蛋白中去除抗体结合位点， 保护性抗原（PA）毒素亚单位。下一代抗毒素开发战略， 这一限制涉及可溶性受体诱饵抑制剂（RDI）的使用;据推测PA不能 因此，RDI应该是有效的，即使对形式 PA被故意改变以抵抗抗体中和。我们最近开发了一种RDI 其具有广泛作用的炭疽治疗剂所需的许多特性：它结合受体结合蛋白， PA的位点，其亲和力与一些主要的治疗性抗体相当（Kd = 0.2nM）;它 阻断通过炭疽毒素的两种已知细胞受体的中毒;其与PA的解离速率非常高， 缓慢（t1/2复合物= 15小时）;它是非免疫原性的;它的生产很容易使用细菌 表达系统;它可以中和PA在化学计量浓度和保护大鼠免受毒素杀伤。 这项研究计划代表了一个全面的战略，推进RDI作为候选疗法， 炭疽热我们将通过破坏其与药物的相互作用来表征和优化其药代动力学特性。 生理配体（胶原IV和层粘连蛋白），并通过利用PEG化和IG融合蛋白方法。 我们还将确定这类抑制剂是否能有效中和PA的抗体耐药形式， 预期此外，我们将确定这类抑制剂是否可以预防由Sterne引起的小鼠疾病 表达野生型或抗体抗性PA的孢子。这些实验将为未来的发展奠定基础。 旨在确定RDI在预防高毒力引起的疾病方面的有效性的研究 B.炭疽病我们预计RDI将是一种有用的炭疽辅助疗法， 与单克隆抗体协同治疗由野生型细菌菌株引起的感染， 时间提供了一个简单的战略，处理工程，武器化的细菌菌株。

项目成果

A receptor-based switch that regulates anthrax toxin pore formation.

• DOI: 10.1371/journal.ppat.1002354
• 发表时间: 2011-12
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Pilpa RM;Bayrhuber M;Marlett JM;Riek R;Young JA
• 通讯作者: Young JA

Delayed toxicity associated with soluble anthrax toxin receptor decoy-Ig fusion protein treatment.

与可溶性炭疽毒素受体诱饵-Ig 融合蛋白治疗相关的延迟毒性。

• DOI: 10.1371/journal.pone.0034611
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Thomas,Diane;Naughton,John;Cote,Christopher;Welkos,Susan;Manchester,Marianne;Young,JohnAT
• 通讯作者: Young,JohnAT