title: Humoral immunity and delayed-type hypersensitivity in healthy subjects treated for 30 days with MK-7123, a selective CXCR2 antagonist.
abstract: Antagonism of the chemokine receptor CXCR2 inhibits neutrophil trafficking and may thus be therapeutic in patients with chronic obstructive pulmonary disease and other lung disorders in which there is substantial infiltration by neutrophils. Here, we report the findings from a randomized, placebo-controlled, double-blind clinical trial of the small-molecule CXCR2 antagonist MK-7123 (formerly SCH 527123) that evaluated potential downstream effects of CXCR2 antagonism on immunogenic competency (B cell antibody response) in the adaptive immune system and delayed-type hypersensitivity (DTH) in healthy subjects (ages 34-65 years) dosed once daily for 30 days either with 30 mg MK-7123 (n=24) or placebo (n=7). Eligible subjects were seronegative for anti-hepatitis A virus (HAV) immunoglobulin G (IgG) and positive for DTH response to intradermal injection of Candida albicans antigen at screening. Subjects were vaccinated for HAV on treatment Day 2. The primary endpoints were anti-HAV IgG titer on Day 30 and DTH response magnitude on Day 27. Pharmacokinetic and safety endpoints were also assessed. We observed that anti-HAV IgG titers and DTH responses did not differ significantly between MK-7123-treated and placebo-treated subjects. Twenty-eight days postvaccination, seroconversion (anti-HAV IgG titer≥10mIU/mL) was observed in 87.5% and 85.7% of MK-7123-treated and placebo-treated subjects, respectively; mean (±SE) titers were 27.3±5.5 and 21.4±4.3mIU/mL, respectively. Treatment with MK-7123 was generally well tolerated. Doses were followed by temporary reductions in absolute peripheral blood neutrophil count. In conclusion, this study found that B cell response and cell-mediated immunity were not altered by CXCR2 antagonism with MK-7123.
authors.affiliation: Covance Clinical Research Unit AG, Allschwil, Basel, Switzeraland.
authors.forename: Michael
authors.initials: M
authors.lastname: Seiberling
authors.forename: Thierry
authors.initials: T
authors.lastname: Kamtchoua
authors.forename: Paul
authors.initials: P
authors.lastname: Stryszak
authors.forename: Xuewen
authors.initials: X
authors.lastname: Ma
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Langdon
authors.forename: Sauzanne
authors.initials: S
authors.lastname: Khalilieh
mesh_terms: D000328:Adult; D000368:Aged; D000917:Antibody Formation / Q000187:drug effects; D001549:Benzamides / Q000009:adverse effects / Q000627:therapeutic use*; D002452:Cell Count; D002478:Cells, Cultured; D003503:Cyclobutanes / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D035922:Hepatitis A Antibodies / Q000097:blood; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000188:drug therapy*; D007111:Immunity, Cellular / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D014611:Vaccination
chemical_list: C516686:2-hydroxy-N,N-dimethyl-3-(2-((1-(5-methylfuran-2-yl)propyl)amino)-3,4-dioxocyclobut-1-enylamino)benzamide; D001549:Benzamides; D003503:Cyclobutanes; D035922:Hepatitis A Antibodies; D023063:Receptors, Interleukin-8B
keywords: Adaptive immunity; CXCR2 antagonist; Cell-mediated immunity; Vaccination