Safety and pharmacokinetics of a chimerized anti-lipoteichoic acid monoclonal antibody in healthy adults

• Published in: International immunopharmacology 2009-05, Vol.9 (5), p.639-644
• Main Authors: Weisman, Leonard E., Fischer, Gerald W., Thackray, Helen M., Johnson, Karen E., Schuman, Richard F., Mandy, George T., Stratton, Beth E., Adams, Karen M., Kramer, William G., Mond, James J.
• Format: Article
• Language: English
• Subjects: Adult; Animals; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - adverse effects; Anti-Bacterial Agents - pharmacokinetics; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - pharmacokinetics; Biological and medical sciences; Chimerized monoclonal antibody; Coagulase negative staphylococci; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Immunogenicity; Injections, Intravenous; Lipopolysaccharides - immunology; Male; Medical sciences; Mice; Middle Aged; Neutrophils - drug effects; Neutrophils - immunology; Neutrophils - metabolism; Neutrophils - microbiology; Neutrophils - pathology; Opsonophagocytic activity; Phagocytosis - drug effects; Phagocytosis - immunology; Pharmacokinetics; Pharmacology. Drug treatments; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - adverse effects; Recombinant Fusion Proteins - pharmacokinetics; Safety; Serum Bactericidal Test; Staphylococcal Infections - immunology; Staphylococcal Infections - therapy; Staphylococcus aureus; Staphylococcus aureus - immunology; Staphylococcus epidermidis; Staphylococcus epidermidis - immunology; Teichoic Acids - immunology
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2009.02.008

A chimerized (murine/human) monoclonal antibody (pagibaximab) against lipoteichoic acid (LTA) and protective in animal models for coagulase-negative staphylococci (CONS) and Staphylococcus aureus bacteremia, was developed for prevention of staphylococcal infection in high-risk populations. This open label two-dose study of a single intravenous dose of 3 or 10 mg/kg of pagibaximab evaluated the safety/tolerability, pharmacokinetics, and opsonophagocytic activity of pagibaximab in healthy adults. Eight participants were enrolled (four in each dose group). No infusion, drug, or dose related adverse events occurred. Serum anti-LTA levels were dose-related; mean concentrations peaked at 87.75 and 259.24 μg/mL for 3 and 10 mg/kg groups, respectively. The half-life (beta) of pagibaximab was approximately 33 days. Opsonophagocytic activity of serum samples on a human clinical isolate of Staphylococcus epidermidis in a standard bacterial killing assay was dose-related, and peaked at a mean of 88.5 and 95.5% at 1:90 dilution for 3 and 10 mg/kg groups, respectively. Serum anti-LTA and opsonophagocytic activity levels exhibited statistically significant correlation. The results suggest that pagibaximab at 3 and 10 mg/kg administered as a single intravenous dose in healthy adults appears to: 1) provide preliminary safety and tolerability data, 2) produce dose-related serum anti-LTA and opsonophagocytic activity levels, 3) have a half-life similar to other immunoglobulin G1 antibodies, 4) exhibit statistically significant correlation between serum anti-LTA and opsonophagocytic activity levels. This study supports conducting safety and pharmacokinetic trials of pagibaximab in populations at high-risk of developing CONS infection.