Therapeutic Human Monoclonal Antibodies Against Staphylococcal Enterotoxin B (SEB

性状（由申请方提供）：葡萄球菌肠毒素B（SE B）是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，并最终导致严重的中毒性休克。疾病控制和预防中心（CDC）将SE B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，没有针对SEB的治疗剂可用于人类使用。该提案旨在临床前开发全人治疗性抗SEB单克隆抗体（hMab）。通过使用人组合抗体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8个克隆进行临床前测试和评价。这些hMab中的几种显示出对SEB的中和活性。研究计划有四个具体目标。在目的1中，基于使用体外增殖测定和体内SEB中毒小鼠模型的广泛研究，将鉴定具有针对SEB中毒和其他相关超抗原的中和活性的先导hMab。将在目标2内在SEB诱导的中毒性休克的小鼠模型中确定先导hMab的治疗功效，以确定先导治疗剂的短列表。在目的3中，如果需要，将通过使用专有诱变技术使先导治疗性抗体经历亲和力成熟，这将产生第二代优化的抗SEB hMab。将对治疗候选物进行生物药理学表征。优化的hMab将在Aim 4内通过人源化转基因小鼠模型和恒河猴气溶胶激发模型进行中毒性休克测试，以鉴定针对SEB中毒的最终临床前治疗候选物。开发的抗体的预期临床应用将是预防性的，以通过即将发生的生物恐怖袭击为高风险个体提供被动免疫，并作为治疗性解毒剂用于治疗已经暴露于SEB的个体。这项提案汇集了来自综合生物治疗公司、美国陆军传染病医学研究所（USAMRIID）、Biocon公司、以及MorphoSys AG及其子公司AbD-Serotec，在抗毒素治疗开发、生物威胁剂的动物研究以及开发全人抗体的新型专有技术方面。

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.