In spite of aggressive antibiotic therapy and supportive care, gram negative pneumonia remains a major cause of death and prolonged hospitalization. To address this unmet need, Inotek is developing an antibody-based strategy that targets flagellin, a critical virulence factor of motile gram negative pathogens. Flagella is required for effective bacterial invasion of epithelium. Moreover, flagellin is a highly potent trigger of NF-kappa B activation and pro-inflammatory gene expression, and thus may contribute to the excessive deleterious host response to regional infection. Both active and passive immunization strategies that target the N-terminal domain of flagellin reduce mortality in LD9O-100 murine models of Serratia marcescens induced acute pneumonia to less than 10 percent. This level of protection is associated with a 90 percent reduction in bacterial cfu in the lung, a 95 percent decrease in pulmonary neutrophil infiltration, and a 50 percent reduction in the incidence of bacteremia. Because the N-terminus is highly conserved, immune responses are cross-protective against a broad spectrum of gram negative pathogens. The central objective of the Phase I SBIR is to obtain proof of principle that anti-N-terminal flagellin mAb's are protective in vivo against a broad spectra of lethal infection.We will test the in vivo protective action of 14 proprietary murine mAb's in a murine model of acute gram negative bacterial pneumonia produced by intratracheal bacterial inoculation of E. coil. Specific outcome variables will include: 1) Pharmacodynamic profile; 2) Therapeutic window of opportunity; and 3) Spectrum of activity against Pseudomonas aeruginosa, Serratia marcescens, and Enterobacter cloacae. In a follow-on Phase II SBIR, we will use the peptide corresponding to the lead epitopes identified in Phase I in order to produce a human mAb.We will then advance the lead mAb technology towards commercialization by 1) optimizing in vitro yield and purity, 2) characterizing in vivo half-life, and 3) performing safety and tolerance studies in two species. These milestones will provide a foundation for IND submission and the first clinical trials of a human anti-flagellin broad-spectrum mAb.
Since there are no marketed anti-inflammatory agents that are safe and effective for the adjunctive therapy of gram negative pnenmocda, it is difficult to predict the future market size and trend. We anticipate, based upon the numbers of hospitalized patients with severe pneumonia, that the market exceeds that for sepsis. Thus, a very conservative estimate of the domestic market may be $200-400 million per annum.
| Murthy, Kanneganti G K; Deb, Amitabha; Goonesekera, Sunali et al. (2004) Identification of conserved domains in Salmonella muenchen flagellin that are essential for its ability to activate TLR5 and to induce an inflammatory response in vitro. J Biol Chem 279:5667-75 |
| Liaudet, Lucas; Szabo, Csaba; Evgenov, Oleg V et al. (2003) Flagellin from gram-negative bacteria is a potent mediator of acute pulmonary inflammation in sepsis. Shock 19:131-7 |
