Immunotherapy of MRSA Osteomyelitis

耐甲氧西林金黄色葡萄球菌(MRSA)每年在美国约80,000人中导致侵袭性感染 尽管有有效对抗耐甲氧西林金黄色葡萄球菌的药物可用，但去年的总死亡率为14%。此外, 甲氧西林可导致大量治疗失败和死亡的侵袭性疾病。 危重病和免疫抑制患者的金黄色葡萄球菌(MSSA)敏感感染。金黄色葡萄球菌是领先的 假体关节感染(PJI)的原因。值得注意的是，全关节置换术(TJA)和 在过去的50年里，创伤手术基本上没有变化。产后感染导致的治疗失败率 金黄色葡萄球菌的感染率高达38%。MRSA的再感染率非常高(15%-40%)，通常需要两个- 分期置换关节成形术。治疗失败率高达33-59%，死亡率为7%-24% 是在两期翻修手术后报告的。因此，考虑到日益增长的负担和疾病的严重性， 抗生素治疗后治疗失败率高，辅助免疫疗法等替代疗法可以 提高治疗成功率是当务之急。我们已经证明了N- 乙酰氨基葡萄糖苷酶(GMD)是金黄色葡萄球菌细胞分裂过程中二次分裂的关键酶。 感染介导的骨侵袭，是骨髓炎的关键步骤。我们开发了一种有效的抗GMD 中和单抗TPH-101，并证明了这种完全人源性抗体在 种植金黄色葡萄球菌骨髓炎小鼠模型及其在翻修手术中的辅助作用 种植相关金黄色葡萄球菌联合万古霉素感染模型的建立。已经建立了 在相关动物模型中的概念证明，在这种直接到第二阶段SBIR的应用下，我们将完成 在复杂的小鼠和兔植入模型中进行严格的安全性、有效性和药代动力学(PK)研究。 相关骨髓炎，完成细胞系和过程开发，与FDA举行IND前会议，以及 完成启用IND的安全性和药代动力学研究。该提案有四个具体目标。在AIM 1我们将去除任何潜在的序列风险，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，我们将开发释放、效力、PK和稳定性的生物分析方法，以及 进行初步的剂量翻译研究。目标3将培育稳定的CHO细胞系以获得高产 制造业。在目标4中，将开发可扩展的制造工艺，生产一批毒物，并 IND前会议将与FDA举行，以寻求对临床前和临床安全计划的反馈。毒理学 Lot将用于动物和人体组织样本的GLP安全性药理学研究。在完成后 这款SBIR产品定位于cGMP的制造、IND的归档和临床开发的启动。

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.