Journal Article

A Phase 1 Study of PAmAb, a Fully Human Monoclonal Antibody against <i>Bacillus anthracis</i> Protective Antigen, in Healthy Volunteers

G. Mani Subramanian, Patrick W. Cronin, Gerald Poley, Andrea Weinstein, Susan M. Stoughton, John Zhong, Ying Ou, Jonathan F. Zmuda, Blaire L. Osborn and William W. Freimuth

in Clinical Infectious Diseases

Published on behalf of Infectious Diseases Society of America

Volume 41, issue 1, pages 12-20
Published in print July 2005 | ISSN: 1058-4838
Published online July 2005 | e-ISSN: 1537-6591 | DOI: http://dx.doi.org/10.1086/430708
A Phase 1 Study of PAmAb, a Fully Human Monoclonal Antibody against Bacillus anthracis Protective Antigen, in Healthy Volunteers

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  • Immunology
  • Public Health and Epidemiology
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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 χ50% 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.

Journal Article.  4001 words.  Illustrated.

Subjects: Infectious Diseases ; Immunology ; Public Health and Epidemiology ; Microbiology

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