Immunotherapy of MRSA Osteomyelitis

MRSA 骨髓炎的免疫治疗

基本信息

批准号：
10595669
负责人：
M Javad Aman
金额：
$ 100万
依托单位：
ABVACC, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-12 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10595669
关键词：
Aman American Animal Model Antibiotic Therapy Antibiotics Antibodies Autolysin Bacterial Adhesins Biology Cell Line Cell Separation Cell Wall Cell physiology Cessation of life Chinese Hamster Ovary Cell Clinical Combined Modality Therapy Communicable Diseases Critical Illness Cyclic GMP Data Death Rate Development Development Plans Disease Dose Drug Kinetics Economic Burden Enzymes Feedback Freedom Fund Raising Funding Agency Genes Glucosaminidase Goals Human Immune Evasion Immunocompromised Host Immunology Immunotherapy Implant Industry Infection Infectious Skin Diseases Investigational New Drug Application Length of Stay Mediating Medical center Methicillin Methicillin Resistance Methods Microbial Biofilms Modeling Monoclonal Antibodies Mus Musculoskeletal N acetylglucosaminidase Operative Surgical Procedures Orthopedics Oryctolagus cuniculus Osteomyelitis Patients Peptidoglycan Periprosthetic joint infection Pharmaceutical Preparations Pharmacology Study Phase Phase I Clinical Trials Physicians Polishes Population Positioning Attribute Prevention Privatization Process Public Health Qualifying Rehabilitation therapy Replacement Arthroplasty Reporting Research Running Safety Second Look Surgery Severity of illness Small Business Innovation Research Grant Staphylococcus aureus Staphylococcus aureus infection Surgical Models Testing Therapeutic Therapeutic Monoclonal Antibodies Tissue Sample Toxicology Translations Treatment Failure Universities Vaccines Vancomycin Vision Work animal tissue antibody test bone invasion burden of illness cell bank clinical development cost effective cross reactivity daughter cell efficacy study experience human pathogen human tissue implant associated infection improved infection rate innovation joint injury manufacture manufacturing process methicillin resistant Staphylococcus aureus method development mid-career faculty mortality mouse model neutralizing monoclonal antibodies pathogen pre-Investigational New Drug meeting pre-clinical product development professor programs safety study septic stable cell line standard of care success synergism translational study trauma surgery

项目摘要

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.

耐甲氧西林金黄色葡萄球菌 (MRSA) 导致每年约 80,000 名美国人遭受侵袭性感染尽管有有效对抗 MRSA 的药物，但 2017 年的总体死亡率为 14%。此外，甲氧西林可能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敏感金黄色葡萄球菌（MSSA）感染。金黄色葡萄球菌是主要的假体关节感染（PJI）的原因。值得注意的是，全关节置换术（TJA）和过去 50 年来，创伤手术基本上没有变化。 PJI 导致的治疗失败率金黄色葡萄球菌感染率高达38%。 MRSA 的再感染率非常高 (15-40%)，通常需要两次感染阶段交换关节置换术。治疗失败率高达 33-59%，死亡率为 7%-24% 两阶段修复手术后有报道。因此，考虑到疾病负担的增加和严重性，抗生素治疗后治疗失败率很高，辅助免疫疗法等替代疗法可以迫切需要提高治疗成功率。我们已经证明了 N-的关键作用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元裂变的关键酶，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 中和单克隆抗体 TPH-101，并证明了这种全人源抗体在植入物引起的金黄色葡萄球菌骨髓炎的小鼠模型及其在翻修手术中的辅助疗效与万古霉素联合使用的植入物相关金黄色葡萄球菌感染模型。已经建立了相关动物模型中的概念验证，根据直接进入第二阶段 SBIR 申请，我们将完成在复杂的小鼠和兔子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、完整细胞系和工艺开发，与 FDA 举行 IND 前会议，以及完成支持 IND 的安全性和药代动力学研究。该提案有四个具体目标。瞄准 1 我们将消除任何潜在的序列缺陷，并在骨科植入物的兔子模型中测试抗体- 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，以及进行初步剂量翻译研究。目标 3 将开发稳定的 CHO 细胞系以实现高产量制造业。在目标 4 中，将开发可扩展的制造工艺、生产毒理学批次以及将与 FDA 举行 IND 前会议，寻求临床前和临床安全计划的反馈。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。完成后在此 SBIR 中，该产品定位于 cGMP 制造、IND 备案和临床开发启动。