Immunotherapy of MRSA Osteomyelitis

耐甲氧西林金黄色葡萄球菌（MRSA）导致侵袭性感染，在大约80,000美国人， 年，总死亡率为14%，尽管有抗MRSA的药物可用。此外，本发明还提供了一种方法， 甲氧西林可导致大量治疗失败和死亡的侵袭性疾病- 敏感S.金黄色葡萄球菌（MSSA）感染的危重病和免疫抑制患者。S. aureus是领先的 人工关节感染（PJI）值得注意的是，全关节置换术（TJA）后的感染率和 创伤外科在过去50年中基本上保持不变。PJIs治疗失败率 由S.金黄色葡萄球菌高达38%。MRSA的再感染率非常高（15-40%），通常需要两次- 分期置换关节成形术。治疗失败率高达33-59%，死亡率为7%-24%， 在二期翻修手术后报告。因此，鉴于日益增加的负担和疾病的严重性， 抗生素治疗后的高治疗失败率，如辅助免疫治疗， 提高治疗成功率是迫切需要的。我们已经证明了N的关键作用- 乙酰氨基葡萄糖苷酶（Gmd）是S.金黄色葡萄球菌细胞分裂期间， 感染介导的骨侵袭，是骨髓炎的关键步骤。我们研制了一种强效抗转基因药物 中和单克隆抗体TPH-101，并证明了这种完全人抗体在 植入物诱导的S.金黄色骨髓炎及其在翻修手术中的辅助疗效 种植体相关S.金黄色葡萄球菌感染联合万古霉素。已经建立了 在相关动物模型中的概念验证，根据本直接进入第II阶段SBIR申请，我们将完成 在复杂的小鼠和家兔模型中进行的严格的安全性、有效性和药代动力学（PK）研究， 相关骨髓炎，完成细胞系和工艺开发，与FDA举行IND前会议， 完成IND启用安全性和药代动力学研究。该提案有四个具体目标。在Aim中 1我们将去除任何潜在的序列负债，并在骨科植入物的兔模型中测试抗体- 相关感染。在目标2中，我们将开发用于放行、效价、PK和稳定性的生物分析方法， 进行初步剂量转换研究。将在目标3中开发稳定的CHO细胞系以获得高产率 制造业在目标4中，将开发可扩展的生产工艺，生产毒理学批次， 将与FDA举行IND前会议，以寻求对临床前和临床安全性计划的反馈。毒理学 该批次将用于动物和人体组织样本的GLP安全药理学研究。完成后 在本SBIR中，该产品定位于cGMP生产、IND备案和临床开发启动。

Methicillin-resistant Staphylococcus aureus (MRSA) causes invasive infections in about 80,000 Americans every year with a 14% overall mortality rate, despite the availability of drugs that are active against MRSA. In addition, a significant number of invasive diseases with treatment failure and mortality can occur as a result of methicillin- sensitive S. aureus (MSSA) infection in critically ill and immunosuppressed patients. S. aureus is the leading cause of prosthetic joint infections (PJI). Remarkably, infection rates following total joint arthroplasty (TJA) and trauma surgery have remained largely unchanged over the last 50 years. Treatment failure rate for PJIs caused by S. aureus is as high as 38%. Reinfection rates from MRSA are very high (15-40%), and often require a two- stage exchange arthroplasty. Treatment failure rates as high as 33-59% and mortality rates of 7%-24% have been reported after two-stage revision surgery. Thus, given the growing burden and the severity of disease and the high rate of treatment failure after antibiotics treatment, alternatives like adjunct immunotherapies that can increase the treatment success are urgently needed. We have demonstrated a key role for N- acetylglucosaminidase (Gmd), a key enzyme in binary fission during S. aureus cellular division, during the infection-mediated invasion of the bone, a critical step in osteomyelitis. We developed a potent anti-Gmd neutralizing monoclonal antibody, TPH-101, and demonstrated the efficacy of this fully human antibody in a murine model of implant-induced S. aureus osteomyelitis as well as its adjunct efficacy in a revision surgery model of implant-associated S. aureus infection in combination with vancomycin. Having already established the proof of concept in relevant animal models, under this Direct to Phase II SBIR application, we will complete rigorous safety, efficacy and pharmacokinetic (PK) studies in sophisticated murine and rabbit models of implant- associated osteomyelitis, complete cell line and process development, hold a pre-IND meeting with FDA, and complete the IND-enabling safety and pharmacokinetic studies. The proposal has fours Specific Aims. In Aim 1 we will remove any potential sequence liabilities and test the antibody in a rabbit model of orthopedic implant- associated infection. In Aim 2 we will develop bioanalytical methods for release, potency, PK, and stability, and conduct preliminary dose translation studies. A stable CHO cell line will be developed in Aim 3 for high yield manufacturing. In Aim 4, a scalable manufacturing process will be developed, a toxicology lot produced, and a pre-IND meeting will be held with FDA to seek feedback on pre-clinical and clinical safety plans. The toxicology lot will be used in GLP-safety pharmacology studies in animals and human tissue samples. Upon completion of this SBIR, the product is positioned for cGMP manufacturing, IND filing and initiation of clinical development.