Receptor Decoy Inhibitor of Anthrax Toxin

炭疽毒素受体诱饵抑制剂

• 批准号: 7751278
• 负责人: MARIANNE MANCHESTER
• 金额: $ 46.89万
• 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 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7751278
• 关键词: Address; Affinity; Anthrax disease; Antibodies; Antibody Binding Sites; Antigens; Antitoxins; Bacillus anthracis; Bacteria; Bacterial Typing; Binding; Binding Sites; Bioterrorism; Categories; Chimeric Proteins; Collagen Type IV; Complex; Development; Disease; Dissociation; Drug Kinetics; Effectiveness; Engineering; Future; Hour; Infection; Intoxication; Laminin; Ligands; Monoclonal Antibodies; Mus; Names; Pathogenesis; Physiological; Principal Investigator; Production; Property; Rattus; Reproduction spores; Research; Resistance; Role; Staging; System; Therapeutic; Therapeutic antibodies; Time; Toxin; United States; Vaccines; Virulent; anthrax toxin; anthrax toxin receptors; base; immunogenic; inhibitor/antagonist; killings; neutralizing antibody; next generation; prevent; programs; receptor; receptor binding; research study

DESCRIPTION (provided by applicant): 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 antibody- based 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.

描述(申请人提供)：芽胞形成细菌炭疽芽孢杆菌引起炭疽，被归类为六类A类制剂之一，被认为是生物武器的主要威胁。由于炭疽毒素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，包括基于单抗的治疗。然而，人们对细菌进行工程改造以避免疫苗保护或抗毒素治疗的简便性有很大的担忧，例如通过从保护性抗原(PA)毒素亚单位中去除抗体结合部位。解决这一局限性的下一代抗毒素开发策略涉及使用可溶性受体诱骗抑制剂(RDI)；推测PA不能被设计成逃避细胞受体识别，因此RDI即使对已被故意改变以抵抗抗体中和的PA形式也应该有效。我们最近开发了一种RDI，它具有广泛作用的炭疽治疗药物所需的许多特性：它与PA的受体结合部位的亲和力与一些主要的治疗性抗体(Kd=0.2 nM)相当；它通过两种已知的细胞炭疽毒素受体来阻断中毒；它与PA的解离速度非常慢(T1/2复合体=15小时)；它不具有免疫原性；它的生产很容易利用细菌表达系统进行缩放；它可以在化学计量浓度下中和PA，并保护大鼠免受毒素杀死。这项研究计划代表了推进RDI作为炭疽候选疗法的综合战略。我们将通过破坏其与生理配体(IV型胶原和层粘连蛋白)的相互作用，以及利用聚乙二醇化和Ig融合蛋白的方法来表征和优化其药代动力学特性。我们还将确定这类抑制剂是否如预期的那样在中和抗体抵抗形式的PA方面有效。此外，我们将确定这种类型的抑制剂是否可以预防由表达野生型或抗体抗性PA的Sterne孢子引起的小鼠疾病。这些实验将为未来旨在确定RDI在预防由高毒力炭疽菌菌株引起的疾病方面的有效性的研究奠定基础。我们预计，RDI将是一种有用的炭疽辅助疗法，可以潜在地与单抗协同治疗由野生型细菌菌株引起的感染，同时为处理工程化、武器化的细菌菌株提供一种直接的策略。