Immunotherapy of MRSA Osteomyelitis

Information

  • Research Project
  • 10253297
  • ApplicationId
    10253297
  • Core Project Number
    R44AI155309
  • Full Project Number
    1R44AI155309-01A1
  • Serial Number
    155309
  • FOA Number
    PA-20-260
  • Sub Project Id
  • Project Start Date
    5/12/2021 - 3 years ago
  • Project End Date
    4/30/2024 - 7 months ago
  • Program Officer Name
    XU, ZUOYU
  • Budget Start Date
    5/12/2021 - 3 years ago
  • Budget End Date
    4/30/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    01
  • Suffix
    A1
  • Award Notice Date
    5/11/2021 - 3 years ago

Immunotherapy of MRSA Osteomyelitis

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.

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    R44
  • Administering IC
    AI
  • Application Type
    1
  • Direct Cost Amount
  • Indirect Cost Amount
  • Total Cost
    1000000
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
  • Funding ICs
    NIAID:1000000\
  • Funding Mechanism
    SBIR-STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    INTEGRATED BIOTHERAPEUTICS, INC.
  • Organization Department
  • Organization DUNS
    601000750
  • Organization City
    ROCKVILLE
  • Organization State
    MD
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    208503855
  • Organization District
    UNITED STATES