Development of anti-LPS therapeutic antibodies for the treatment of Pseudomonas aeruginosa infections - SUMMARY The goal of this proposal is to develop therapeutic antibodies for the treatment of multidrug resistant (MDR) P. aeruginosa infections, with an emphasis on sepsis. With the rise in antimicrobial resistance around the world we are running out of therapeutic options against MDR P. aeruginosa. Our laboratory has identified a potential solution to address this problem: a therapeutic antibody cocktail that targets the lipopolysaccharide of P. aeruginosa. One of the antibodies present in the cocktail (WVU-VDC-S3D4, or S3D4 for short) completely protects mice against lethal sepsis, preventing bacterial dissemination and cytokine storm. This antibody is also more potent than vaccination with a P. aeruginosa whole cell vaccine or passive immunization with serum from whole cell vaccinated mice. Most interestingly, S3D4 is also capable of directly killing P. aeruginosa in vitro in the absence of complement or immune cells. In this proposal, we will characterize the mechanism of action of S3D4, formulate it in an LPS multivalent antibody cocktail, and evaluate efficacy against MDR P. aeruginosa. To do this, we will evaluate host and bacterial factors involved in S3D4 function (Aims 1 and 2). We will then combine it as cocktail with three additional antibodies that target the 6 LPS serogroups that cause 87% of P. aeruginosa bloodstream infection. Efficacy in vitro and in vivo will be evaluated with MDR clinical isolates (Aim 3). We will also evaluate efficacy against P. aeruginosa biofilms. We hypothesize that a multivalent anti-LPS cocktail of antibodies, alone or in combination with standard of care antibiotics, will be efficacious for the prevention and treatment of MDR P. aeruginosa sepsis. By the completion of these studies, we anticipate to elucidate the mechanism of action of a novel class of antibodies that can directly kill P. aeruginosa in vitro, which will help with the production of additional antibodies with similar functions against other MDR organisms. We will also produce proof of concept data to support the generation antibody therapy against P. aeruginosa infections. Altogether, this project will generate important knowledge to improve the lives of patients affected by this MDR bacterium.
