Immunotherapy of MRSA Osteomyelitis

MRSA 骨髓炎的免疫治疗

• 批准号: 10253297
• 负责人: M Javad Aman
• 金额: $ 100万
• 依托单位: INTEGRATED BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-12 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10253297
• 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; Joint Prosthesis; 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; Pharmaceutical Preparations; Pharmacology Study; Phase; Phase I Clinical Trials; Physicians; Polishes; Population; Positioning Attribute; Prevention; Privatization; Process; Public Health; Rehabilitation therapy; Replacement Arthroplasty; Reporting; Research; Running; Safety; Severity of illness; Small Business Innovation Research Grant; Staphylococcus aureus; Staphylococcus aureus infection; 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 infection; joint injury; manufacturing process; meetings; methicillin resistant Staphylococcus aureus; method development; mid-career faculty; mortality; mouse model; neutralizing monoclonal antibodies; pathogen; pre-clinical; product development; professor; programs; safety study; septic; stable cell line; standard of care; success; synergism; trauma surgery; vaccine-induced antibodies

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）每年在大约8万美国人中引起侵袭性感染