The Novel Immunotherapeutic Oligodeoxynucleotide IMT504 Protects Neutropenic Animals from Fatal Pseudomonas aeruginosa Bacteremia and Sepsis

• Published in: Antimicrobial agents and chemotherapy Vol. 59; no. 2; pp. 1225 - 1229
• Main Authors: Chahin, Abdullah, Opal, Steven M., Zorzopulos, Jorge, Jobes, David V., Migdady, Yazan, Yamamoto, Michelle, Parejo, Nicholas, Palardy, John E., Horn, David L.
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.02.2015
• Subjects: Animals; Bacteremia; Bacteremia - microbiology; Bacteremia - prevention & control; Experimental Therapeutics; Female; Neutropenia; Neutropenia - drug therapy; Oligodeoxyribonucleotides; Oligodeoxyribonucleotides - therapeutic use; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - pathogenicity; Rats; Sepsis; Sepsis - microbiology; Sepsis - prevention & control
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/AAC.03923-14

IMT504 is a novel immunomodulatory oligonucleotide that has shown immunotherapeutic properties in early preclinical and clinical studies. IMT504 was tested in a neutropenic rat model of Pseudomonas aeruginosa bacteremia and sepsis. This animal system recapitulates many of the pathological processes found in neutropenic patients with Gram-negative, bacterial infections. The research was conducted in the setting of an academic research laboratory. The test subjects were Sprague-Dawley rats. Animals were rendered neutropenic by administration of cyclophosphamide, colonized with P. aeruginosa by oral feeding, and then randomized to receive IMT504 over a range of doses and treatment regimens representing early and late therapeutic interventions. IMT504 immunotherapy conferred a significant survival advantage over the 12-day study period compared with the results seen with placebo-treated animals when the therapy was administered at the onset of neutropenia and even in the absence of antibiotics and after the onset of fever and systemic infection. Notably, even late salvage IMT504 monotherapy was highly effective (13/14 surviving rats with IMT504 therapy versus 2/14 controls, P = <0.001). Moreover, late salvage IMT504 monotherapy was as effective as antibiotic therapy (13/14 surviving rats versus 21/21 rats, P = 0.88). In addition, no antagonism or loss of therapeutic efficacy was noted with combination therapy of IMT504 plus antibiotics. IMT504 immunotherapy provides a remarkable survival advantage in bacteremia and sepsis in neutropenic animals and deserves further study as a new treatment option in patients with, or at risk for, severe Gram-negative bacterial infections and sepsis.