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.

芽孢杆菌炭疽杆菌引起炭疽，被列为六种 A 类细菌之一 被视为生物武器主要威胁的制剂。由于其在疾病发病机制中的关键作用， 目前正在开发多种抑制炭疽毒素的策略，包括基于单克隆抗体的策略 疗法。然而，人们非常担心这种细菌是否容易被感染。 旨在避免疫苗保护或抗毒素治疗，例如通过去除抗体结合位点 保护性抗原（PA）毒素亚基。下一代抗毒素开发策略，旨在解决 这种限制涉及使用可溶性受体诱饵抑制剂（RDI）； PA 大概不能 旨在逃避细胞受体识别，因此 RDI 即使针对形式也应该有效 PA 已被故意改变以抵抗抗体中和。我们最近开发了 RDI 它具有广泛作用的炭疽治疗所需的许多特性：它与受体结合 PA 位点的亲和力与一些领先的治疗抗体相当 (Kd = 0.2nM)；它 通过两种已知的炭疽毒素细胞受体阻断中毒；它与 PA 的解离率非常高 慢（t1/2 复合= 15 小时）；它是非免疫原性的；使用细菌可以轻松扩大其生产规模 表达系统；它可以中和化学计量浓度的 PA，并保护大鼠免受毒素杀死。 该研究计划代表了推进 RDI 作为候选疗法的综合策略 炭疽病。我们将通过破坏其与其相互作用来表征和优化其药代动力学特性。 生理配体（IV 胶原蛋白和层粘连蛋白），并利用聚乙二醇化和 Ig 融合蛋白方法。 我们还将确定此类抑制剂是否能有效中和抗体抗性形式的 PA，因为 预期的。此外，我们将确定此类抑制剂是否可以预防由斯特恩引起的小鼠疾病 表达野生型或抗体抗性 PA 的孢子。这些实验将为未来奠定基础 旨在确定 RDI 在预防高毒力致病菌引起的疾病方面的有效性的研究 炭疽芽孢杆菌菌株。我们预计 RDI 将成为一种有用的炭疽辅助疗法，有可能 与单克隆抗体协同治疗野生型菌株引起的感染，同时 时间提供了一种处理工程化、武器化细菌菌株的简单策略。

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