title: Safety and pharmacokinetics of a chimerized anti-lipoteichoic acid monoclonal antibody in healthy adults.
abstract: 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 microg/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.
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. lweisman@bcm.edu
authors.forename: Leonard E
authors.initials: LE
authors.lastname: Weisman
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Fischer
authors.forename: Helen M
authors.initials: HM
authors.lastname: Thackray
authors.forename: Karen E
authors.initials: KE
authors.lastname: Johnson
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schuman
authors.forename: George T
authors.initials: GT
authors.lastname: Mandy
authors.forename: Beth E
authors.initials: BE
authors.lastname: Stratton
authors.forename: Karen M
authors.initials: KM
authors.lastname: Adams
authors.forename: William G
authors.initials: WG
authors.lastname: Kramer
authors.forename: James J
authors.initials: JJ
authors.lastname: Mond
mesh_terms: D000328:Adult; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008070:Lipopolysaccharides / Q000276:immunology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D015610:Serum Bactericidal Test; D013203:Staphylococcal Infections / Q000276:immunology / Q000628:therapy*; D013211:Staphylococcus aureus / Q000276:immunology*; D013212:Staphylococcus epidermidis / Q000276:immunology*; D013682:Teichoic Acids / Q000276:immunology*
chemical_list: D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D008070:Lipopolysaccharides; D011993:Recombinant Fusion Proteins; D013682:Teichoic Acids; C524976:pagibaximab; C009900:lipoteichoic acid