Therapeutic Antibodies for Biofilm Infections

Abstract The CDC estimates thatof clinically significant drug resistant bacterial infections are drug refractory due to a change in physiological state of pathogens associated with biofilm formationTRLis a high affinitypMnative human monoclonal antibodymAbthat disrupts biofilms by extracting a key bacterial scaffolding proteinThe epitope is highly conserved in the target protein homologs across a broad spectrum of gram positive and gram negative bacteriaincluding all ESKAPE pathogensThe released bacteria regain sensitivity to antibioticsBiofilm disruption has been demonstrated in vitro for Staphylococcus aureus and for several gram negative speciesPseudomonas aeruginosaAcinetobacter baumanniiKlebsiella pneumoniaeIn vivoTRLin combination with an antibiotic vsantibiotic alone has shown statistically significant efficacy against methicillin resistant SaureusMRSAin two animal modelsinfected implants in mice and infective endocarditis in ratsand against a drug resistant clinical isolate of Abaumannii in a mouse model of soft tissue infectionClinical toxicity risk is lowas the epitope is not present in the human proteome and the mAb was cloned from a healthy human donorA 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 NIAIDThe major goal of the SBIR funding is to develop a Master Cell BankMCBproducing TRLat commercially useful levels along with development of product specific assaysExpression at the pooled CHO cell transfection stage is within the expected range prior to subcloning and optimization of upstream and downstream processingThe remaining SBIR work has low risk of failure and will be completed in QWe now seek CRP funding to complete the IND enabling preclinical development including toxicology studiesadditional animal efficacy studiesand manufacturing of sufficient material for Phaseand Phasehuman clinical trialsWith CRP funding projected to start shortly after the end of the SBIR Phase II fundingwe anticipate IND filing withinmonths after receipt of CRP fundingNo SBIR or CRP funding will be used for actual clinical trial expenses Project Narrative This project will complete the IND enabling preclinical development of TRLa 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 antibioticsThis Commercialization Readiness ProgramCRPproposal is a follow on to an SBIR Phase II project that will be completed prior to start of CRP fundingThe major goal of the CRP funding is to manufacture sufficient clinical material for Phaseand PhasetrialsTRLhas low toxicity risk and offers substantial potential clinical benefit against a wide range of infections that are currently very difficult to treat