National surveillance data confirm that 50% of A. baumannii isolates from US intensive care units are extreme drug resistance (XDR), far higher than other pathogens. At least 23,000 and 75,000 cases of XDR A. baumannii infections occur annually in the US and globally (in developed countries), respectively. These infections result in ~10,000 and 30,000 deaths and excess healthcare costs of $390 million and $742 million in the US and globally, annually. Furthermore, in contrast to other resistant bacteria, virtually no antibiotics are in the pipeline to deal with XDR A. baumannii. New prevention and treatment strategies are critically needed. We will develop a therapeutic monoclonal antibody to treat A. baumannii infections, as an adjunct to antibiotics. In a series of pathogenesis studies, we found that A. baumannii virulence was driven by an initial evasion of innate immune-mediated clearance, resulting in sustained LPS-TLR4 activation that drove sepsis syndrome. Thus enhancement of innate immune mediated clearance was a promising immune-therapeutic strategy to improve outcomes from infection. Furthermore, passive immunization with polyclonal immune serum targeting A. baumannii improved survival of infected recipient mice, validating the approach. We have a MAb, BioAIM1 that binds to the surface of multiple strains of A. baumannii as well as polyclonal immune serum, and is nearly completely protective in otherwise fatal models of XDR A. baumannii bacteremic sepsis and aspiration pneumonia, the most common clinical syndromes of A. baumannii infection. During phase I of the funded STTR grant, we humanized the MAb. In phase II, we seek to advance it towards IND filing:
Aim 1. Establish GMP manufacturing for our candidate MAbs. GMP scale up will be established by STC Biologics. The GMP process will include establishment of a master cell bank, completion of scale up including an initial GMP-like manufacturing run followed by repeat runs and a final 50 L reactor run, as well as stability studies. We will confirm the in vitro and in vivo activity of the material produced. Our highly experienced team, which has taken prior companies to IPO and taken drugs through NDA/BLA, will manage the vendor.
Aim 2. Complete pre-clinical toxicity studies to support an IND application. Toxicity studies have been designed based on FDA guidance, and their execution will be contracted to a qualified vendor. We will hold a pre-IND meeting with the FDA to confirm our plans for toxicity studies and the future phase I clinical tria. Completion of pre-clinical toxicity studies using GMP-like material and will be targeted for year 2. Upon completion of funding we will be positioned to file an IND that will allow subsequent initiation of a phase I clinical trial. The impact of the MAb once developed will be to markedly improve survival and morbidity from highly lethal, XDR and pan-drug resistant (PDR) A. baumannii infections. The impact will be particularly great given the absence of new antibiotics in development to treat A. baumannii.
Acinetobacter baumannii is one of the most antibiotic-resistant bacteria that infects and kills patients in the US and globally. The antibiotic pipeline s virtually barren for new options to treat these deadly, virtually untreatable infections. We seek t develop immune therapy, using antibodies to help the immune system clear the bacteria, improving outcomes from these infections.
| Nielsen, Travis B; Yan, Jun; Luna, Brian et al. (2018) Murine Oropharyngeal Aspiration Model of Ventilator-associated and Hospital-acquired Bacterial Pneumonia. J Vis Exp : |
| Shin, Woo Shik; Bergstrom, Alexander; Bonomo, Robert A et al. (2017) Discovery of 1-Hydroxypyridine-2(1H)-thione-6-carboxylic Acid as a First-in-Class Low-Cytotoxic Nanomolar Metallo ?-Lactamase Inhibitor. ChemMedChem 12:845-849 |
| Wong, Darren; Nielsen, Travis B; Bonomo, Robert A et al. (2017) Clinical and Pathophysiological Overview of Acinetobacter Infections: a Century of Challenges. Clin Microbiol Rev 30:409-447 |
| Nielsen, Travis B; Pantapalangkoor, Paul; Yan, Jun et al. (2017) Diabetes Exacerbates Infection via Hyperinflammation by Signaling through TLR4 and RAGE. MBio 8: |
| Spellberg, Brad; Bonomo, Robert A (2016) Editorial Commentary: Ceftazidime-Avibactam and Carbapenem-Resistant Enterobacteriaceae: ""We're Gonna Need a Bigger Boat"". Clin Infect Dis 63:1619-1621 |
