A phase 1 study of PAmAb, a fully human monoclonal antibody against Bacillus anthracis protective antigen, in healthy volunteers

被引:76
|
作者
Subramanian, GM
Cronin, PW
Poley, G
Weinstein, A
Stoughton, SM
Zhong, J
Ou, Y
Zmuda, JF
Osborn, BL
Freimuth, WW
机构
[1] Human Genome Sci, Rockville, MD 20850 USA
[2] PAREXEL Int, Baltimore, MD USA
关键词
D O I
10.1086/430708
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background. Inhibition of the binding of Bacillus anthracis protective antigen (PA) to its cellular receptor can abrogate the downstream toxin-mediated deleterious effects of the anthrax toxin. A fully human monoclonal antibody against B. anthracis PA, PAmAb, was previously shown to provide a survival advantage in rabbit and monkey models of inhalational anthrax. Methods. A randomized, single-blind, placebo-controlled, dose-escalation study with 105 healthy volunteers was conducted to evaluate the safety, pharmacokinetics, and biological activity of PAmAb. Subjects received PAmAb or placebo as a single intramuscular injection ( 11 subjects/cohort) or intravenous infusion ( 10 subjects/cohort). Three intramuscular dose levels (0.3, 1.0, and 3.0 mg/kg) and 5 intravenous dose levels ( 1.0, 3.0, 10, 20, and 40 mg/kg) were studied. Two separate intramuscular injection sites ( gluteus maximus and vastus lateralis) were evaluated in the cohorts ( hereafter, the "IM-GM" and "IM-VL" cohorts, respectively). Results. PAmAb was well tolerated, with no dose-limiting adverse events. All adverse events were transient and mild to moderate in incidence and/or severity. The pharmacokinetics of PAmAb were linear within each route and site of administration but were significantly different between the IM-GM and IM-VL cohorts. The mean terminal elimination half-life ranged from 15 to 19 days. The bioavailability of PAmAb is similar to 50% for IM-GM injection and 71%-85% for IM-VL injection. The biological activity of PAmAb in serum, assessed using a cyclic adenosine monophosphate assay, correlated with serum concentrations. Conclusions. PAmAb is safe, well tolerated, and bioavailable after a single intramuscular or intravenous dose, which supports further clinical development of PAmAb as a novel therapeutic agent for inhalational anthrax.
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页码:12 / 20
页数:9
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