Evaluating Cloudbreak Molecule for Protection Against Acinetobacter Pneumonia
APR 15, 2019 | MICHAELA FLEMING
Asmultidrug-resistant organisms are an urgent public health threat, resistance due to gram-negative bacilli, including Acinetobacter baumannii (AB), are growing endemic across the globe and novel methods are needed to treat these infections.
These infections are particularly concerning as septicemia, which is triggered by lipopolysaccharide (LPS), can result in vascular leak, tissue edema, organ failure, and death and is a common manifestation of gram-negative bacilli.
The bifunctional Cloudbreak molecule, Compound A, consists of a Targeting Moiety, a small molecule which binds LPS, and is joined to an Effector Moiety, an Fc domain of human IgG1 to engage host Fcγ and FcRn receptors, via a stable linker.
To evaluate the activity of Compound A against AB in vitro and in vivo, investigators from the Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center conducted a study.
The findings of the study were presented in a poster presentation atthe European Congress for Clinical Microbiology and Infectious Diseases (ECCMID 2019).
Contagion® spoke to Ashraf Ibrahim, PhD, who presented the poster at the meeting, to learn more about Compound A.
The investigators used a trans-well permeability assay to evaluate the role of Compound A in enhancing the vascular integrity of human umbilical vein endothelial cells (HUVECs) infected with AB.
Further, Compound A was evaluated for efficacy in protecting against AB pneumonia in neutropenic mice (cyclophosphamide [200 mg/kg] and cortisone acetate [500 mg/kg] on day -2, +3, and +8 relative to infection). Treatment with 10 mg/kg Compound A was initiated 3 hours following infection and continued through day +7 daily or every other day and was compared to colistin treatment (2.5 mg/kg bid, daily). The endpoints that were assessed by the investigators were mouse survival by Day +21 and lung CFU by Day +4.
The study found thatCompound A at 0.1, 0.5, and 1.0 μM reduced trans-membrane HUVECs leakage caused by AB by ~50-85% (P<0.0001). Additionally, the treatment of mice with Compound A led to enhanced survival comparable to colistin treatment versus placebo (40% and 70% for Compound A daily and every other, respectively, 60% for colistin, vs. 0% survival for placebo p<0.03 for all treatments).
Lastly, Compound A daily treatment resulted in almost complete clearance of the mice’s lungs, while Compound A every other day or colistin daily treatment resulted in 4- and 3-log reduction of lung bacterial burden, respectively (P<0.0001).
Based on these findings, the investigators concluded thatCompound A has potent activity against AB mouse infection possibly by a dual killing mechanism and by reducing LPS-induced vascular leak. In order to evaluate Compound A as a novel treatment for multidrug-resistant gram-negative bacilli more research is needed.
Big advances in treatment can't make up for an inability to stop new infections, which number 5,000 per day worldwide.
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