title: Pharmacokinetics and safety in cynomolgus monkeys of a monoclonal antibody targeting human scavenger receptor class B type-1 for hepatitis C treatment.
abstract: BACKGROUND
  Scavenger receptor class B type-1 (SR-B1) is one of the many receptors used by HCV to infect hepatocytes. It is used by the virus not only to directly infect cells but also to facilitate cell-to-cell transmission of the virus. Agents such as anti-human SR-B1 (anti-hSR-B1) antibodies represent potential therapeutics for the treatment of HCV infections. The purpose of this study was to evaluate the safety and pharmacokinetics of an anti-hSR-B1 antibody (Seq2) in cynomolgus monkeys.
  
  
  METHODS
  The antibody was administered intravenously at 1, 10 and 100 mg/kg body weight; blood samples were taken pre- and post-dose to evaluate the pharmacokinetic profile and blood chemistry. Safety was assessed during treatment and the animals were sacrificed post-treatment for pathological assessment and liver antibody-receptor occupancy determination.
  
  
  RESULTS
  Following administration of Seq2 antibody to cynomolgus monkeys a non-linear pharmacokinetic profile was observed. The clearance of the antibody decreased from 2 to 0.3 ml/h/kg with increasing doses from 1 to 100 mg/kg, respectively, and the antibody half-life varied from 62 to 218 h for the same doses. An increase in total cholesterol and high-density lipoprotein cholesterol levels after antibody administration was observed, with a good correlation between liver receptor occupancy and dose.
  
  
  CONCLUSIONS
  The pharmacokinetics and toxicology results were in accordance with the pharmacology of the antibody mechanism. The elevation of total cholesterol was dose-dependent and did not exceed a twofold increase. The safety study indicated no adverse effects during the treatment or in the pathology analysis at any of the doses tested.
authors.affiliation: Antivirals Group, Pfizer Inc., Sandwich, UK. v.flores@btinternet.com.
authors.forename: M Victoria
authors.initials: MV
authors.lastname: Flores
authors.forename: Romuald G
authors.initials: RG
authors.lastname: Corbau
authors.forename: Silvia
authors.initials: S
authors.lastname: Guionaud
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001774:Blood Chemical Analysis; D018929:Cell Culture Techniques; D002460:Cell Line; D005260:Female; D016174:Hepacivirus; D006526:Hepatitis C / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D009500:Neutralization Tests; D051122:Scavenger Receptors, Class B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B