Therapeutic Human Monoclonal Antibodies Against Staphylococcal Enterotoxin B (SEB

描述(申请人提供)：葡萄球菌肠毒素B(SEB)是由许多金黄色葡萄球菌分离株产生的原型肠毒素。SEB导致T淋巴细胞的多克隆激活，导致促炎介质的大量释放，最终导致严重的中毒性休克。SEB被疾病控制和预防中心(CDC)视为B类选择药物。SEB也是食物中毒和中毒性休克综合征的主要原因。目前，还没有针对SEB的治疗方法可供人类使用。这项建议旨在临床前开发完全人类治疗性抗SEB单抗(HMabs)。通过使用人类组合抗体库和噬菌体展示方法，鉴定了一组全人抗SEB抗体。初步鉴定导致选择了8个克隆进行临床前测试和评估。其中几种抗体对SEB具有中和活性。研究计划设计了4个具体目标。在目标1中，基于体外增殖试验和体内SEB中毒小鼠模型的广泛研究，将鉴定具有抗SEB中毒和其他相关超抗原的中和活性的先导型hMAbs。在SEB诱导的中毒性休克小鼠模型中，将在AIM 2中确定铅hMabs的治疗效果，以确定一系列铅治疗方法。在目标3中，如有必要，先导治疗性抗体将通过使用专有突变技术进行亲和力成熟，这将导致第二代优化的抗SEB hMabs。治疗候选药物将具有生物物理学特征。优化后的hMabs将在Aim 4内通过人源化转基因小鼠模型和针对中毒性休克的恒河猴气溶胶挑战模型进行测试，以确定针对SEB中毒的最终临床前治疗候选方案。所开发的抗体的预期临床应用将既是预防性的，通过迫在眉睫的生物恐怖袭击向高风险个人提供被动免疫，也将作为治疗已经暴露于SEB的个人的治疗解毒剂。这项建议汇集了综合生物治疗公司、美国陆军传染病医学研究所(USAMRIID)、Biocon公司以及MorPhoSys公司及其子公司Abd-Serotec在抗毒素治疗开发、使用生物治疗剂的动物研究以及用于开发完全人类抗体的新专利技术方面的专业知识。

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.