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.