Therapeutic Human Monoclonal Antibodies Against Staphylococcal Enterotoxin B (SEB

抗葡萄球菌肠毒素 B 的治疗性人单克隆抗体 (SEB

• 批准号: 7454587
• 负责人: M Javad Aman
• 金额: $ 71.92万
• 依托单位: INTEGRATED BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7454587
• 关键词: Aerosols; Affinity; Animals; Antibodies; Antibody Affinity; Antidotes; Antigen-Antibody Complex; Antitoxins; Biological; Biological Assay; Biological Response Modifier Therapy; Categories; Cells; Centers for Disease Control and Prevention (U.S.); Communicable Diseases; Cyclic GMP; Development; Development Plans; Dose; Enterotoxins; Epitopes; Evaluation; Exotoxins; Food Poisoning; Funding Mechanisms; Generations; Goals; Half-Life; Human; In Vitro; Inbred BALB C Mice; Individual; Inflammatory; Intoxication; Investigational New Drug Application; Kinetics; Lead; Length; Libraries; Living Wills; Macaca mulatta; Mediator of activation protein; Medical; Modeling; Modification; Monoclonal Antibodies; Mus; Mutagenesis; Numbers; Passive Immunity; Phage Display; Range; Rate; Research; Research Institute; Research Proposals; Risk; Series; Serum; Site; Specificity; Staphylococcal Enterotoxin B; Staphylococcus aureus; Structure; Superantigens; Surface Plasmon Resonance; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic antibodies; Toxic Shock Syndrome; Toxic effect; Toxin; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; Treatment Protocols; United States Food and Drug Administration; base; biothreat; clinical application; cohort; combinatorial; comparative; design; efficacy trial; evaluation/testing; glycosylation; human monoclonal antibodies; improved; in vivo; mouse model; nonhuman primate; novel; pre-clinical; prophylactic; prototype; research study; response; scale up; success; technology development

DESCRIPTION (provided by applicant): Staphylococcal enterotoxin B (SEB) is a prototype enterotoxin produced by many isolates of Staphylococcus aureus. SEB causes polyclonal activation of T lymphocytes resulting in massive release of pro-inflammatory mediators and culminating in severe toxic shock. SEB is considered by the Centers for Disease Control and Prevention (CDC) as a category B select agent. SEB is also a major cause of food poisoning and toxic shock syndrome. Currently, there are no therapeutics available against SEB for human use. This proposal is aimed at preclinical development of fully human therapeutic anti-SEB monoclonal antibodies (hMabs). By using a human combinatorial antibody library and a phage display approach, a cohort of fully human antibodies against SEB were identified. Preliminary characterization has led to the selection of eight clones for pre-clinical testing and evaluation. Several of these hMabs displayed neutralizing activity towards SEB. The research plan is designed in 4 Specific Aims. In Aim 1, lead hMabs with neutralizing activity against SEB intoxication and other related superantigens will be identified based upon extensive studies using in vitro proliferation assays and an in vivo mouse model of SEB intoxication. Therapeutic efficacy of the lead hMabs will be determined within Aim 2 in a mouse model of SEB-induced toxic shock to identify a short list of lead therapeutics. In Aim 3, the lead therapeutic antibodies will be subjected to affinity maturation, if necessary, by using a proprietary mutagenesis technology that will result in a second generation of optimized anti-SEB hMabs. Therapeutic candidates will be biophysically characterized. The optimized hMabs will be tested within Aim 4 via a humanized transgenic mouse model and rhesus aerosol challenge model for toxic shock to identify the final preclinical therapeutic candidate against SEB intoxication. The envisioned clinical applications of the developed antibody will be both prophylactic to provide passive immunity to individuals at high risk via an imminent bioterror attack, and as a therapeutic antidote for treatment of individuals already exposed to SEB. This proposal brings together expertise from Integrated Biotherapeutics Inc, the US Army Medical Research Institute of Infectious Diseases (USAMRIID), Biocon, Inc., as well as MorphoSys AG and its subsidiary AbD-Serotec, in anti-toxin therapeutic development, animal studies with biothreat agents, and a novel proprietary technology for development of fully human antibodies.

描述（由申请人提供）：葡萄球菌肠毒素B（SEB）是由金黄色葡萄球菌的许多分离物产生的原型肠毒素。 SEB导致T淋巴细胞的多克隆激活，导致大量促进介质释放，并在严重的毒性休克中达到顶点。疾病控制与预防中心（CDC）将SEB视为B类选择的药物。 SEB还是食物中毒和有毒休克综合征的主要原因。目前，针对人类使用的SEB尚无治疗剂。该提案旨在临床前发展人类治疗性抗SEB单克隆抗体（HMABS）。通过使用人类组合抗体库和噬菌体显示方法，可以确定针对SEB的一系列完全人类的抗体。初步表征导致选择了八个克隆进行临床前测试和评估。这些HMAB中的几个显示出对SEB的中和活性。该研究计划以4个特定目标设计。在AIM 1中，将基于使用体外增殖测定法和SEB中毒的体内小鼠模型来确定具有中和活性和其他相关超抗原活性和其他相关超抗原的铅HMAB。铅HMAB的治疗功效将在SEB诱导的毒性休克的小鼠模型中确定在AIM 2中，以识别铅疗法的简短列表。在AIM 3中，铅治疗抗体将在必要时使用专有的诱变技术进行亲和力成熟，该技术将导致第二代优化的抗SEB HMAB。治疗候选者将以生物物理表征。优化的HMAB将通过人源化的转基因小鼠模型和恒河状气溶胶挑战模型在AIM 4中进行测试，以识别针对SEB中毒的最终临床前治疗候选者。开发抗体的临床应用将是预防性的，可以通过迫在眉睫的生物疗法攻击对处于高风险的个体的被动免疫，也可以作为治疗已经暴露于SEB的个体的治疗解毒剂。该提议汇集了来自综合生物治疗剂Inc，美国陆军医学研究所（USAMRIID），Biocon，Inc。，以及Morphosys AG及其子公司ABD-Serotec，在抗毒素治疗性发展中，具有BiotheReat Agents的动物研究，并具有新颖的人类技术，并具有全新的人类技术。