IC14,a CD14 specific monoclonal antibody,is a potential treatment for patients with severe sepsis

Abstract

CD14 is a pattern recognition receptor for the bacterial cell wall components from Gram-positive and Gram-negative bacteria as well as mycobacteria. Binding of lipopolysaccharide (LPS) or other cell wall constituents to CD14 initiates signal transduction through the Toll-like receptors resulting in the release of pro-inflammatory cytokines and the initiation of the systemic inflammatory response. In rabbits and non-human primates, CD14 specific antibodies were shown to attenuate responses to LPS or Escherichia coli challenge including pro-inflammatory cytokine release, acute lung injury, hypotension and changes in lung, liver, spleen and adrenal gland morphology. In healthy human subjects, single doses of a chimeric CD14 antibody (IC14) have been shown to be well tolerated and result in a dose-related degree of saturation of CD14 receptors on monocytes and granulocytes. Pretreatment of healthy subjects with IC14 2 h prior to LPS resulted in an attenuation of the LPS-induced fever, clinical symptoms, and leukocyte activation and degranulation. IC14 inhibited the release of TNF-α, IL-6, and IL-10 and delayed the release of sTNFR_I and IL-1ra. Further studies are in progress to characterize the safety and clinical pharmacology of IC14 in patients with severe sepsis.

References

Pugin J. , Heumann D. , Tomasz A. et al. CD14 is a pattern recognition receptor. Immunity 1994; 1: 509—516.

Stelter F. , Bernheiden M. , Menzel R. et al. The molecular basis for therapeutic concepts utilizing CD14 . Prog Clin Biol Res 1998; 397: 301—313.

Wright SD CD14 and the innate response to bacteria. J Immunol 1995; 155: 6—8.

Takeuchi O. , Hoshino K. , Kawai T. et al. Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cell wall components. Immunity 1999; 11: 443—451.

Schwandner R. , Dziarski R. , Wesche H. , Rothe M. , Kirschning CJ Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by Toll-like receptor 2. J Biol Chem 1999; 274: 17406—17409.

Chow JC , Young DW , Golenbock DT , Christ WJ , Gusovsky F. Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction . J Biol Chem 1999; 274: 10689—10692.

St John RC , Dorinsky PM An overview of multiple organ dysfunction syndrome. J Lab Clin Med 1994; 124: 478—483.

Marsh CB , Wewers MD The pathogenesis of sepsis. Factors that modulate the response to Gram-negative bacterial infection. Clin Chest Med 1996; 17: 183—197.

Schimke J. , Mathison J. , Morgiewicz J. , Ulevitch RJ Anti-CD14 mAb treatment provides therapeutic benefit after in vivo exposure to endotoxin. Proc Natl Acad Sci USA 1998; 95: 13875—13880.

10.

Leturcq DJ , Moriarty AM , Talbott G. et al. Antibodies against CD14 protects primates from endotoxin-induced shock. J Clin Invest 1996; 98: 1533—1538.

11.

Verbon A. , Dekkers P. , Pribble J. et al. Inhibition of the systemic inflammatory response by a recombinant chimeric anti-CD14 monoclonal antibody during human endotoxemia. Shock 2000; 13 (Suppl 1): 168.

12.

Frevert CW , Matute-Bello G. , Skerrett SJ et al. Effect of CD14 blockade in rabbits with Escherichia coli pneumonia and sepsis. J Immunol 2000; 164: 5439—5445.

13.

Wenneras C. , Ave P. , Huerre M. et al. Blockade of CD14 increases Shigella-mediated invasion and tissue destruction. J Immunol 2000; 164: 3214—3221.