In the last decade, Acinetobacter baumannii has emerged as one of the most highly antibiotic-resistant pathogens in the United States (US) and throughout the world. These infections are increasingly prevalent and highly lethal, killing 50-60% of those infected. Worse, strains of A. baumannii that no known antibiotic will kill have now emerged, and will continue to increase in frequency given the lack of antibiotics in development to treat A. baumannii. Given the tremendous scientific barriers to developing new antibiotics to treat A. baumannii and the economic market failure of antibiotics, new treatments are critically needed for this bacteria. We propose to develop a passive vaccine targeting A. baumannii (i.e., an antibody that can be administered to patients with A. baumannii infection). Our data indicate that antibody-based therapy is a promising strategy to treat A. baumannii infections. We first identified a protein that the bacteria expresses on its surface called OmpA (Outer membrane protein A) that appeared to be a suitable target for a vaccine. We then found that when recombinant OmpA was injected into mice as an active vaccine, and subsequently the vaccinated or control mice were infected with A. baumannii, the vaccine protected mice from otherwise lethal extreme drug resistant (XDR) A. baumannii infection. Next, we discovered that the mechanism of vaccine- mediated efficacy was induction of protective antibodies. We then raised 5 distinct types of monoclonal antibodies (MAbs) against OmpA isolated from A. baumannii. These MAbs enhance opsonophagocytic killing of A. baumannii in vitro and effectively protected mice given a lethal infection with XDR A. baumannii. While these MAbs are a promising new therapy for XDR A. baumannii infections, the feasibility of further clinical development will hinge upon successful humanization of the antibodies. Mouse MAbs cannot be used to treat humans, because humans mount an immune reaction to mouse MAbs that can cause rapid removal of the MAbs (hence lower efficacy), systemic inflammation, severe allergic reactions, and even a risk for death. The humanization process prevents these undesirable effects. We therefore propose to humanize the MAbs while retaining their anti-A. baumannii activity (as verified both in vitro and in vivo) in two AIMS: 1) Humanize 3 lead candidate MAbs, with class switching to human IgG3;2) Define an optimally effective humanized MAb regimen based on in vitro surface binding and bacterial killing, and in vivo efficacy in a mouse model of A. baumannii infection. A. baumannii infections pose a grave public health threat that urgently demands development of new treatments, but no new antibiotics to treat these infections will likely be available in the coming decade. MAbs hold great promise to treat A. baumannii infections. We propose conservative milestones (feasibility criteria) that are part of a standard, methodical development pathway for our unique MAbs as a novel treatment for such infections. Progression to Phase II depends on humanization of the MAbs without loss of efficacy.
In the last decade, Acinetobacter baumannii has emerged as one of the most highly antibiotic-resistant and deadly pathogens in the United States (US) and throughout the world. Given the tremendous scientific barriers to developing new antibiotics to treat A. baumannii and the economic market failure of antibiotics, new treatments are critically needed for this bacterium. We have developed mouse monoclonal antibodies that successfully treat mice given otherwise lethal infections of A. baumannii, and seek to humanize the antibodies as a critical first step towards translation to clinical development.
|Russo, Thomas A; Spellberg, Brad; Johnson, James R (2016) Important Complexities of the Antivirulence Target Paradigm: A Novel Ostensibly Resistance-Avoiding Approach for Treating Infections. J Infect Dis 213:901-3|
|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|
|Bruhn, Kevin W; Dekitani, Ken; Nielsen, Travis B et al. (2016) Ly6G-mediated depletion of neutrophils is dependent on macrophages. Results Immunol 6:5-7|
|Bruhn, Kevin W; Spellberg, Brad (2015) Transferrin-mediated iron sequestration as a novel therapy for bacterial and fungal infections. Curr Opin Microbiol 27:57-61|
|Bruhn, Kevin W; Pantapalangkoor, Paul; Nielsen, Travis et al. (2015) Host fate is rapidly determined by innate effector-microbial interactions during Acinetobacter baumannii bacteremia. J Infect Dis 211:1296-305|
|Spellberg, Brad; Bonomo, Robert A (2015) Combination Therapy for Extreme Drug-Resistant Acinetobacter baumannii: Ready for Prime Time? Crit Care Med 43:1332-4|
|Nielsen, Travis B; Bruhn, Kevin W; Pantapalangkoor, Paul et al. (2015) Cryopreservation of virulent Acinetobacter baumannii to reduce variability of in vivo studies. BMC Microbiol 15:252|
|Spellberg, Brad; Gilbert, David N (2014) The future of antibiotics and resistance: a tribute to a career of leadership by John Bartlett. Clin Infect Dis 59 Suppl 2:S71-5|
|Spellberg, Brad; Bonomo, Robert A (2014) The deadly impact of extreme drug resistance in Acinetobacter baumannii. Crit Care Med 42:1289-91|
|Spellberg, Brad; Rex, John H (2013) The value of single-pathogen antibacterial agents. Nat Rev Drug Discov 12:963|
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