The CDC estimates that 65-80% of clinically significant drug resistant bacterial infections are drug refractory due to a change in physiological state of pathogens associated with biofilm formation. TRL1068 is a high affinity (100 pM) native human monoclonal antibody (mAb) that disrupts biofilms by extracting a key bacterial scaffolding protein. The epitope is highly conserved in the target protein homologs across a broad spectrum of gram positive and gram negative bacteria, including all ESKAPE pathogens. The released bacteria regain sensitivity to antibiotics. Biofilm disruption has been demonstrated in vitro for Staphylococcus aureus and for several gram negative species: Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae. In vivo, TRL1068 in combination with an antibiotic vs. antibiotic alone has shown statistically significant efficacy against methicillin resistant S. aureus (MRSA) in two animal models (infected implants in mice and infective endocarditis in rats) and against a drug resistant clinical isolate of A. baumannii in a mouse model of soft tissue infection. Clinical toxicity risk is low, as the epitope is not present in the human proteome and the mAb was cloned from a healthy human donor. A successful pre-IND meeting with the FDA has been held and IND-enabling development activities are underway by an experienced team funded in part by a Phase II SBIR grant from NIAID. The major goal of the SBIR funding is to develop a Master Cell Bank (MCB) producing TRL1068 at commercially useful levels along with development of product specific assays. Expression at the pooled CHO cell transfection stage is within the expected range prior to subcloning and optimization of upstream and downstream processing. The remaining SBIR work has low risk of failure and will be completed in Q3 2017. We now seek CRP funding to complete the IND-enabling preclinical development including toxicology studies, additional animal efficacy studies, and manufacturing of sufficient material for Phase 1 and Phase 2 human clinical trials. With CRP funding projected to start shortly after the end of the SBIR Phase II funding, we anticipate IND filing within 30 months after receipt of CRP funding. No SBIR or CRP funding will be used for actual clinical trial expenses.
This project will complete the IND-enabling preclinical development of TRL1068, a native human monoclonal antibody that extracts a key scaffolding protein from bacterial biofilms leading to the bacteria becoming qualitatively more susceptible to killing by conventional antibiotics. This Commercialization Readiness Program (CRP) proposal is a follow-on to an SBIR Phase II project that will be completed prior to start of CRP funding. The major goal of the CRP funding is to manufacture sufficient clinical material for Phase 1 and Phase 2 trials. TRL1068 has low toxicity risk and offers substantial potential clinical benefit against a wide range of infections that are currently very difficult to treat.
|Xiong, Yan Q; Estellés, Angeles; Li, L et al. (2017) A Human Biofilm-Disrupting Monoclonal Antibody Potentiates Antibiotic Efficacy in Rodent Models of both Staphylococcus aureus and Acinetobacter baumannii Infections. Antimicrob Agents Chemother 61:|