Therapeutic Human Monoclonal Antibodies Against Staphylococcal Enterotoxin B (SEB

描述（由申请人提供）：葡萄球菌肠毒素B （SEB）是一种由许多金黄色葡萄球菌分离株产生的原型肠毒素。SEB引起T淋巴细胞的多克隆活化，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类选择剂。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。该建议旨在临床前开发全人类治疗性抗seb单克隆抗体（hmab）。利用人组合抗体文库和噬菌体展示方法，鉴定了一组针对SEB的全人抗体。初步表征导致选择八个克隆进行临床前测试和评估。其中一些hmab对SEB表现出中和活性。研究计划分为4个具体目标。在Aim 1中，将通过使用体外增殖试验和体内SEB中毒小鼠模型进行广泛的研究，确定具有中和SEB中毒和其他相关超抗原活性的铅单克隆抗体。铅单克隆抗体的治疗效果将在seb诱导的中毒性休克小鼠模型的Aim 2中确定，以确定铅治疗的短列表。在Aim 3中，如有必要，将通过使用专有的诱变技术对先导治疗抗体进行亲和成熟，从而产生第二代优化的抗seb单克隆抗体。治疗候选者将进行生物物理表征。优化后的单克隆抗体将在Aim 4中通过人源化转基因小鼠模型和中毒性休克恒河猴气溶胶攻击模型进行测试，以确定针对SEB中毒的最终临床前治疗候选药物。所开发抗体的预期临床应用将是预防性的，为即将发生的生物恐怖袭击中的高风险个体提供被动免疫，并作为治疗性解毒剂治疗已经暴露于SEB的个体。该提案汇集了综合生物疗法公司、美国陆军传染病医学研究所（USAMRIID）、Biocon公司、MorphoSys AG公司及其子公司abd - sertec公司在抗毒素治疗开发、生物威胁剂动物研究和开发全人抗体的新型专有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.