Human antibodies for therapeutic intervention of staph enterotoxin B exposure

用于葡萄球菌肠毒素 B 暴露治疗干预的人类抗体

• 批准号: 7483115
• 负责人: Luigi Grasso
• 金额: $ 71.92万
• 依托单位: MORPHOTEK, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483115
• 关键词: Address; Advanced Development; Aerosols; Affinity; Animal Model; Antibodies; Antibody Formation; Biological; Biological Assay; Biological Warfare; Cell Line; Cells; Chemistry; Chinese Hamster Ovary Cell; Clinical; Clinical Protocols; Contracts; Cooperative Research and Development Agreement; Development; Diagnostic; Dose; Drug Kinetics; Feeds; Fermentation; Generations; Guanosine Monophosphate; Guidelines; HLA-DQ8 antigen; Hour; Human; Human Activities; Human Cell Line; Human Development; Hybridomas; Immunohistochemistry; In Vitro; Lethal Dose 50; Letters; Macaca mulatta; Maximum Tolerated Dose; Methods; Modeling; Names; Performance; Pharmaceutical Preparations; Process; Production; Rattus; Request for Applications; Research; Research Personnel; Rodent; Safety; Staging; Staphylococcal Enterotoxin B; Structure; T-Cell Proliferation; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Toxicology; Toxin; Transgenic Organisms; United States Food and Drug Administration; Work; biodefense; cell bank; cross reactivity; cytokine; design; human tissue; improved; in vivo; innovation; man; manufacturing process; mouse model; nonhuman primate; pre-clinical; prevent; programs; therapeutic vaccine

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.

描述（由申请人提供）： 该研究计划与能够中和体内中和葡萄球菌肠毒素B（SEB）的抗体的临床前开发有关。该提案的最终目的是准备在2010年之前向FDA提交IND，以进行人类抗SEB MABS（HASMS）的临床开发。 Morphotek和Usamriid一直在合作研究与开发协议下合作，以产生创新的研究，以推动针对SEB以及其他生物乳化毒素的特定治疗剂的开发。 Morphotek已经确定了至少两个可以阻止体内SEB活性的HASM。该提案的目的涉及提交的所有要求的所有要求，包括但不限于：拟议治疗方法的理由和理由；动物模型的功效；我们抗体的毒理学和安全参数；化学，制造和控制（CMC）部分；临床方案的设计。该提案正在响应申请请求（RFA），题为“生物粘液素毒素的治疗和诊断疗法的合作研究合作伙伴关系”，其中SEB是本RFA中包含的生物粘剂毒素之一。需要开发能够预防或逆转SEB毒性的疫苗和治疗策略，并且在重要性方面，本申请列出了我们认为是一项精心设计的结构化计划，可以将我们的HASM从当前的临床前阶段推向3年的临床发展。在该工作计划中，一个目标是通过使用Morphotek的抗体优化技术来进一步提高当前HASM的效力，并找到hasms组合和比率，从而允许降低HASM剂量（例如，人类中的<7 mg/kg）或增加其中性力量（例如，其中度功能（例如，块> 1,000人LD50）。一个主要目的是证明对气溶胶SEB挑战的恒河猴的生存，并在4小时后用HASMS治疗。为了研究HASM的安全性，将在大鼠和cynomolgus中进行毒理学研究，并将使用GLP的免疫组织化学评估潜在的HASMS对正常人体组织的交叉反应性。将优化制造HASM的过程，以实现> 0.5克/L的滴度，并生成GMP材料以支持毒理学研究。