607. Monoclonal Antibodies Targeting Flagellin Attenuate Mortality in a Lethal Model of Pneumonia Driven by Multi-Drug Resistant Pseudomonas Aeruginosa
Session: Poster Abstract Session: Novel Antimicrobial Agents
Friday, October 21, 2011
Room: Poster Hall B1
Background: A major public health crisis is impending due to the paucity of anti-bacterials capable of combatting Pseudomonas Aeruginosa (PA), especially those strains exhibiting a multi-drug resistant (MDR) phenotype. Monoclonal antibodies (mAbs) represent a highly innovative therapeutic approach to tackle PA and could be used as either a monotherapy or co-therapy with existing antibiotics to prevent and treat lethal PA infections. 

Methods: Mouse, chimeric, human and bispecific mAbs were prepared using classical technologies that target PA flagellin. To investigate in-vitro recognition profiles, mouse mAbs were taken for a) ELISA screening versus ~ 100 PA bacterial strains; b) ELISA screening versus recombinantly-expressed targets; c) Affinity determinations via BIACore. Furthermore, mAb biological activities were assessed by inhibition of bacterial motility in soft agar impregnated with mAb. In in-vivo studies using a LD80 mouse model of pneumonia driven by a Multi-Drug Resistant (MDR) PA strain, the ability of mouse and human mAbs in preventing mortality was assessed following i.v. administration of mAbs injected 1 hr after infection. Their biological effects were compared with imipenem in head-to-head studies.    

Results: Mouse and follow-up chimeric mAbs bound respective target proteins at affinities of 1-3 nM. Mouse mAbs targeting PA flagellin type A and B demonstrated universal reactivity to all PA strains screened. Furthermore, a fully human mAb targeting PA flagellin type B demonstrated 97% reactivity to 35 PA strains currently screened. In the pneumonia model, administration of a mouse mAb targeting PA flagellin type B markedly improved survival with 100%, 81% and 72% survival at 1, 2 and 3 days respectively post-infection. This dramatic improvement superceded imipenem-treated animals, with only 30% survival in these animals at 72 hours post-infection.

Conclusion: These pre-clinical data lay credence that neutralizing mAbs targeting PA flagellin might represent a highly novel and desperately needed immunotherapeutic approach to prevent and treat lethal PA infections, including MDR's, in the critical care arena.  


Subject Category: A. Antimicrobial agents and Resistance

Lewis Neville, PhD1, Azmi Adawi, MSc1 and Salvatore Cuzzocrea, PhD2, (1)Lostam BioPharmaceuticals Ltd, Nazareth, Israel, (2)Clinical and Experimental Medicine and Pharmacology, University of Messina , Messina, Italy

Disclosures:

L. Neville, None

A. Adawi, None

S. Cuzzocrea, None

Findings in the abstracts are embargoed until 12:01 a.m. EST Thursday, Oct. 20 with the exception of research findings presented at IDSA press conferences.