title: Safety, pharmacokinetics, and antiviral activity of HGS004, a novel fully human IgG4 monoclonal antibody against CCR5, in HIV-1-infected patients.
abstract: BACKGROUND
  HGS004 is a fully human immunoglobulin (Ig) G4 monoclonal antibody against CC chemokine receptor 5 (CCR5) with robust in vitro activity against a diverse panel of CCR5-tropic human immunodeficiency virus type 1 (HIV-1) isolates.
  
  
  METHODS
  A single-blind, randomized, placebo-controlled study was conducted in patients infected with CCR5-tropic HIV-1 to evaluate the safety, pharmacokinetics, and antiviral activity of HGS004. Sixty-three subjects were randomized into 5 dose cohorts (0.4, 2, 8, 20, and 40 mg/kg) and received a single intravenous dose of HGS004 or placebo.
  
  
  RESULTS
  HGS004 was well tolerated, and no dose-limiting toxicities were observed. Pharmacokinetics were nonlinear across the 0.4-40-mg/kg dose range, with dose-proportional increases in maximum concentration, although the area under the curve increased more than proportionally to dose. High levels of receptor occupancy were observed for up to 28 days in the higher-dose cohorts. Plasma HIV-1 RNA reductions of >1 log(10) at day 14 were observed in 14 (54%) of 26 subjects in the 8-, 20-, and 40-mg/kg cohorts. In the 40-mg/kg cohort, 4 of 10 subjects had a >1 log(10) HIV-1 RNA reduction at day 28. Drug concentrations relative to isolate sensitivity (the ratio of the concentration at day 14 to IC(90)) predicted antiviral response on day 14.
  
  
  CONCLUSIONS
  HGS004 is safe and well tolerated and demonstrates meaningful antiviral activity when administered to patients infected with CCR5-tropic HIV-1.
authors.affiliation: Quest Clinical Research, San Francisco, CA 94115, USA. drjay@questclinical.com
authors.forename: Jacob
authors.initials: J
authors.lastname: Lalezari
authors.forename: Gopal K
authors.initials: GK
authors.lastname: Yadavalli
authors.forename: Michael
authors.initials: M
authors.lastname: Para
authors.forename: Gary
authors.initials: G
authors.lastname: Richmond
authors.forename: Edwin
authors.initials: E
authors.lastname: Dejesus
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Brown
authors.forename: Wendy
authors.initials: W
authors.lastname: Cai
authors.forename: Cecil
authors.initials: C
authors.lastname: Chen
authors.forename: John
authors.initials: J
authors.lastname: Zhong
authors.forename: Lu Anne
authors.initials: LA
authors.lastname: Novello
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lederman
authors.forename: G Mani
authors.initials: GM
authors.lastname: Subramanian
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000187:drug effects; D019713:Receptors, CCR5 / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D012367:RNA, Viral; D019713:Receptors, CCR5