Human antibodies for therapeutic intervention of staph enterotoxin B exposure

描述(由申请人提供)： 该研究计划涉及体内能够中和葡萄球菌肠毒素B(SEB)的抗体的临床前开发。这项提案的最终目标是准备在2010年之前向FDA提交IND，用于人类抗SEB单抗(HASM)的临床开发。MorPhotek和USAMRIID一直在根据合作研究和开发协议进行合作，以产生创新研究，以推动针对SEB和其他生物减毒毒素的治疗方法的开发。MorPhotek已经确定至少有两种HASM可以在体内阻断SEB的活性。该提案的目的涉及提交IND的所有要求，包括但不限于：拟议治疗方法的理由和理由；动物模型的有效性；我们抗体的毒理学和安全性参数(S)；化学、制造和对照(CMC)部分；临床方案的设计。该提案是对题为“生物防御毒素治疗和诊断合作研究伙伴关系”的申请(RFA)的回应，根据该申请，SEB是包括在本RFA中的生物防御毒素之一。有相当大的需要开发能够预防或逆转SEB毒性的疫苗和治疗策略，就意义而言，这项申请列出了我们认为是精心设计的、结构化的计划，以在3年内将我们的HASM从目前的临床前阶段推进到临床开发。在这项工作计划中，一个目标是通过使用MorPhotek名为形态发生学的抗体优化技术来增加现有HASM的亲和力来进一步提高它们的效力，并找到能够降低HASM剂量(例如人类体内7毫克/公斤)或增加其中和能力的HASM组合和比率(例如，阻断&1,000人LD50)。一个主要目标是证明用气雾剂SEB挑战恒河猴并在4小时后用HASM治疗的恒河猴的存活率。为了研究HASM的安全性，将在大鼠和食蟹猴身上进行毒理学研究，并将在GLP下使用免疫组织化学方法评估HASM与正常人体组织的潜在交叉反应。将对HASM的制造工艺进行优化，以达到&gt；0.5克/L滴度，并将产生GMP材料，以支持毒理学研究。

DESCRIPTION (provided by applicant): This research plan relates to the preclinical development of antibodies capable of neutralizing staphylococcal enterotoxin B (SEB) in vivo. The ultimate objective of this proposal is to prepare for submission of an IND to the FDA by the year 2010 for the clinical development of Human Anti-SEB MAbs (HASMs). Morphotek and USAMRIID have been collaborating under a Cooperative Research and Development Agreement to generate innovative research that will advance the development of therapeutics specific for SEB, as well as other biowarfare toxins. Morphotek has identified at least two HASMs that can block SEB activity in vivo. The aims of this proposal address all the requirements for an IND submission including but not limited to: justification and rationale of the proposed therapeutic approach; efficacy in animal models; toxicology and safety parameters of our antibodies(s); chemistry, manufacturing and controls (CMC) section; design of clinical protocol. This proposal is responding to a Request for Application (RFA) entitled "Cooperative Research Partnerships into Therapeutics and Diagnostics for Biodefense Toxins", whereby SEB is one of the biodefense toxins included in this RFA. There is considerable need to develop vaccines and therapeutic strategies capable of preventing or reverse SEB toxicity, and with regard to significance, this application lays out what we believe is a well designed, structured plan to advance our HASMs from their current preclinical stage to clinical development in 3 years. In this work plan, one objective is to further improve the potency of the current HASMs by increasing their affinities using Morphotek's antibody optimization technology named morphogenics, and to find HASMs combinations and ratios that would allow lowering the HASMs dose (e.g. <7 mg/kg in man) or increase their neutralization power (e.g. block >1,000 human LD50). One major objective is to demonstrate survival of rhesus monkeys challenged with aerosol SEB and treated 4 hours later with HASMs. To study the safety of HASMs, toxicology studies will be conducted in rats and cynomolgus, and potential HASMs crossreactivity to normal human tissues will be assessed using immunohistochemistry under GLP. The process for the manufacturing of HASMs will be optimized to achieve >0.5 gram/L titers and GMP material will be generated to support toxicology studies.