A phase 1 study of PAmAb, a fully human monoclonal antibody against Bacillus anthracis 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, William W. Freimuth

Research output: Contribution to journalArticle

Abstract

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 ∼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.

Original languageEnglish (US)
Pages (from-to)12-20
Number of pages9
JournalClinical Infectious Diseases
Volume41
Issue number1
DOIs
StatePublished - Jul 1 2005
Externally publishedYes

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Anthrax
Healthy Volunteers
Intramuscular Injections
Monoclonal Antibodies
Pharmacokinetics
Placebos
Injections
Quadriceps Muscle
Serum
Intravenous Infusions
Cyclic AMP
Biological Availability
Haplorhini
Half-Life
Rabbits
Safety
Survival
Incidence
anthrax toxin
Therapeutics

ASJC Scopus subject areas

  • Immunology

Cite this

Subramanian, G. M., Cronin, P. W., Poley, G., Weinstein, A., Stoughton, S. M., Zhong, J., ... Freimuth, W. W. (2005). A phase 1 study of PAmAb, a fully human monoclonal antibody against Bacillus anthracis protective antigen, in healthy volunteers. Clinical Infectious Diseases, 41(1), 12-20. https://doi.org/10.1086/430708

A phase 1 study of PAmAb, a fully human monoclonal antibody against Bacillus anthracis protective antigen, in healthy volunteers. / Subramanian, G. Mani; Cronin, Patrick W.; Poley, Gerald; Weinstein, Andrea; Stoughton, Susan M.; Zhong, John; Ou, Ying; Zmuda, Jonathan F.; Osborn, Blaire L.; Freimuth, William W.

In: Clinical Infectious Diseases, Vol. 41, No. 1, 01.07.2005, p. 12-20.

Research output: Contribution to journalArticle

Subramanian, GM, Cronin, PW, Poley, G, Weinstein, A, Stoughton, SM, Zhong, J, Ou, Y, Zmuda, JF, Osborn, BL & Freimuth, WW 2005, 'A phase 1 study of PAmAb, a fully human monoclonal antibody against Bacillus anthracis protective antigen, in healthy volunteers', Clinical Infectious Diseases, vol. 41, no. 1, pp. 12-20. https://doi.org/10.1086/430708
Subramanian, G. Mani ; Cronin, Patrick W. ; Poley, Gerald ; Weinstein, Andrea ; Stoughton, Susan M. ; Zhong, John ; Ou, Ying ; Zmuda, Jonathan F. ; Osborn, Blaire L. ; Freimuth, William W. / A phase 1 study of PAmAb, a fully human monoclonal antibody against Bacillus anthracis protective antigen, in healthy volunteers. In: Clinical Infectious Diseases. 2005 ; Vol. 41, No. 1. pp. 12-20.
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AU - Subramanian, G. Mani

AU - Cronin, Patrick W.

AU - Poley, Gerald

AU - Weinstein, Andrea

AU - Stoughton, Susan M.

AU - Zhong, John

AU - Ou, Ying

AU - Zmuda, Jonathan F.

AU - Osborn, Blaire L.

AU - Freimuth, William W.

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N2 - 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 ∼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.

AB - 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 ∼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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