Antibody therapy for serious bacterial infections using polyclonal immune antitoxin or anti-capsule horse serum actually predates small molecule antibiotic use. However, for reasons of safety, convenient empirical use, and cost, the development of broader-spectrum antibiotics rapidly supplanted the use of immune serum. But drug resistance is quickly reducing the number of effective antibiotics available for treatment of severe bacterial infections while advances in human monoclonal antibody (mAb) technologies have led to reconsideration of immunotherapies. Therefore, passive immunotherapies could be effective in preventing or treating high-risk infections caused by drug-resistant bacterial pathogens, such as Pseudomonas aeruginosa, a highly adaptable opportunistic bacterium. Our target antigens for this proposal, the outer membrane proteins OprF and OprI, were chosen because of sequence conservation among clinical isolates and their use as vaccine antigens in several clinical trials. Sorrento Therapeutics, Inc. has developed proprietary technologies, namely its G-MAB(R) library for selection of fully human antibodies as well as "antibody formulated drug conjugate" (AfDC) methodology for generation of targeted micelles. We propose to generate and evaluate anti-OpfF/I mAbs as well as AfDCs, i.e. colistin sulfate/azithromycin-containing micelles linked to selected anti-P. aeruginosa mAbs. The studies will be performed together with our academic collaborator Dr. Daniel Wozniak (Ohio State University). The most promising mAbs and AfDCs will be thoroughly evaluated in vitro and in vivo for their ability to prevent and/or treat local as well as systemic P. aeruginosa infection. Specifically, the projects of our STTR Advanced Technology Phase I grant application are: Project 1 - In vitro evaluation and prioritization of the selected human anti-OprF/I mAbs; Project 2 - Generation and in vitro evaluation of anti-Pseudomonas AfDCs; Project 3 - In vivo evaluation of mAbs/AfDCs in murine and porcine P. aeruginosa infection models. The proposed product, a fully human anti-P. aeruginosa mAb immunotherapy or an AfDC as targeted antibiotic delivery vehicle, would be an effective and safe stand-alone and/or member of a "cocktail" therapeutic option for prevention or treatment of P. aeruginosa infections.
Public Health Relevance Statement: Public Health Relevance: Advances in human monoclonal antibody (mAb) technologies might enable development of passive immunotherapies for prevention or treatment of high-risk infections caused by drug-resistant bacteria, such as Pseudomonas aeruginosa. Our proposed product will be a fully human anti-P. aeruginosa mAb immunotherapy or an antibody-mediated targeted antibiotic delivery vehicle as effective and safe stand-alone and/or member of a "cocktail" therapeutic option for prevention or treatment of P. aeruginosa infections.
NIH Spending Category: Biotechnology; Clinical Research; Immunization; Infectious Diseases; Prevention
Project Terms: Acute; Affinity; analytical method; Antibiotics; Antibodies; Antibody Therapy; Antigen Targeting; Antitoxins; Applications Grants; Azithromycin; Bacteria; Bacterial Infections; base; Binding (Molecular Function); Biochemical; Biological Assay; biophysical properties; capsule (pharmacologic); Cells; Chronic; Clinical; Clinical Trials; Colistin; cost; Data; Deltastab; Development; Drug Delivery Systems; Drug resistance; drug resistant bacteria; efficacy evaluation; Equus caballus; Evaluation; Family suidae; Future; Generations; Growth; Health; high risk; Human; human monoclonal antibodies; Immune; Immune Sera; Immunotherapy; In Vitro; in vivo; Infection; Inorganic Sulfates; Killings; Laboratories; Lead; Libraries; Link; Lung; Mediating; member; Membrane Proteins; method development; Methodology; Micelles; Microbial Biofilms; Modeling; Monoclonal Antibodies; Mus; Ohio; Organ failure; particle; Passive Immunotherapy; pathogen; Patients; Pharmaceutical Preparations; Phase; pre-clinical; prevent; Prevention; Property; Pseudomonas; Pseudomonas aeruginosa; Safety; Serum; Small Business Technology Transfer Research; small molecule; Technology; Therapeutic; Treatment Efficacy; Universities; Unspecified or Sulfate Ion Sulfates; Vaccine Antigen; wound
