Safety, pharmacokinetics, and antiviral activity of HGS004, a novel fully human IgG4 monoclonal antibody against CCR5, in HIV-1-infected patients.
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.
Lalezari
Jacob
J
Quest Clinical Research, San Francisco, CA 94115, USA. drjay@questclinical.com
Yadavalli
Gopal K
GK
Para
Michael
M
Richmond
Gary
G
Dejesus
Edwin
E
Brown
Stephen J
SJ
Cai
Wendy
W
Chen
Cecil
C
Zhong
John
J
Novello
Lu Anne
LA
Lederman
Michael M
MM
Subramanian
G Mani
GM
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*
D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D012367:RNA, Viral; D019713:Receptors, CCR5