TY - JOUR
T1 - Safety, pharmacokinetics, and antiviral activity of HGS004, a novel fully human IgG4 monoclonal antibody against CCR5, in HIV-1-infected patients
AU - Lalezari, Jacob
AU - Yadavalli, Gopal K.
AU - Para, Michael
AU - Richmond, Gary
AU - DeJesus, Edwin
AU - Brown, Stephen J.
AU - Cai, Wendy
AU - Chen, Cecil
AU - Zhong, John
AU - Novello, Lu Anne
AU - Lederman, Michael M.
AU - Subramanian, G. Mani
PY - 2008/3/1
Y1 - 2008/3/1
N2 - 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 log10 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 log10 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.
AB - 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 log10 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 log10 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.
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U2 - 10.1086/527327
DO - 10.1086/527327
M3 - Article
C2 - 18266604
AN - SCOPUS:40549092975
VL - 197
SP - 721
EP - 727
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
SN - 0022-1899
IS - 5
ER -