Evaluation of the safety of recombinant P-selectin glycoprotein ligand-immunoglobulin G fusion protein in experimental models of localized and systemic infection

P-selectin is a major component in the early interaction between platelets, endothelial cells, and inflammatory cells in the initial phases of the inn ate immune response. The major ligand for P-selectin is P-selectin glycopro tein ligand-1 (PSGL-1) and this ligand is expressed on the surface of monoc yte, lymphocyte, and neutrophil membranes. A truncated form of recombinant human P-selectin glycoprotein ligand-1 has been covalently linked to immuno globulin G (rPSGL-Ig) and this fusion peptide functions as a competitive in hibitor of PSGL-1. As an inhibitor of neutrophil-endothelial cell adherence , rPSGL-Ig is in early clinical development for the treatment of ischemia r eperfusion injury. To determine the potential for deleterious effects from inhibition in P-selectin-mediated neutrophil attachment in the presence of bacterial infection, the effects of therapeutic doses of rPSGL-Ig were test ed in three standard laboratory sepsis models. The experimental models incl uded: the murine systemic Listeria monocytogenes infection model, the Pseud omonas aeruginosa bacteremia model in neutropenic rats, and the cecal ligat ion and puncture (CLP)-induced peritonitis model in rats. Recombinant human PSGL-Ig had no adverse effects on mortality or immune clearance in systemi c bacterial infection in any of the three infection models. The PSGL-1 inhi bitor did significantly decrease local neutrophil infiltration and bacteria l clearance in the peritoneum following CLP, but this did not increase the systemic levels of proinflammatory cytokines, the quantitative levels of ba cteremia, or the overall mortality rate following CLP. The results indicate that rPSGL-Ig did not exacerbate infection in these experimental sepsis mo dels.