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

  1. G. Mani Subramanian1,
  2. Patrick W. Cronin1,
  3. Gerald Poley2,
  4. Andrea Weinstein2,
  5. Susan M. Stoughton1,
  6. John Zhong1,
  7. Ying Ou1,
  8. Jonathan F. Zmuda1,
  9. Blaire L. Osborn1, and
  10. William W. Freimuth1
  1. 1Human Genome Sciences, Rockville, and PAREXEL International, Baltimore, Maryland
  2. 2PAREXEL International, Baltimore, Maryland
  1. Reprints or correspondence: Dr. Mani Subramanian, Human Genome Sciences, 14200 Shady Grove Rd., Rockville, MD 20850 (Mani_Subramanian{at}hgsi.com).
 
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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 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.

Anthrax is caused by infection with Bacillus anthracis, a gram-positive, spore-forming bacterium. Anthrax spores lend themselves well to aerosolization and resist environmental degradation; thus, they represent one of the greatest threats in biological warfare [1]. The spread of anthrax spores through the US mail system in 2001 prompted the US Postal Service to order anthrax testing at >200 mail centers along the East Coast and random checks nationwide. More than 10,000 people were prescribed antibiotics to combat real or potential exposure to anthrax [2]. This deliberate distribution of bacterial spores resulted in 5 deaths among the 11 individuals who contracted inhalational anthrax.

Although antibiotics and vaccines are effective, these modalities have their limitations. The need for up to 60 days of antibiotic therapy tends to decrease compliance, as seen in the treatment associated with the 2001 attacks, for which the adherence rate was estimated to be 42% [3, 4]. Vaccination is effective in preventing disease, but the current vaccine approved by the US Food and Drug Administration requires repeated administration and at least 4 weeks for the development of protective titers [5, 6]. Mortality rates are high when treatment is initiated after the onset of symptoms [7]; thus, there exists a need for improved therapies to augment available treatment options for inhalational anthrax.

The anthrax toxin is a tripartite toxin that contains enzymatic and binding moieties. The lethal factor (LF) and edema factor (EF) proteins function as the enzymatic moiety of the toxin, whereas the protective antigen (PA) protein functions as the binding moiety [1]. The PA protein first binds to its cell-surface receptor and, after proteolytic cleavage, multimerizes into a heptameric barrel structure to which LF and EF bind with high affinity. Internalization of this complex by receptor-mediated endocytosis formation of a membrane-spanning pore allows the bound EF and LF proteins to be translocated to the cytosol, where they exert their toxic effects. Thus, inhibition of PA binding to its cellular receptor can abrogate the downstream toxin-mediated deleterious effects of the anthrax toxin.

PAmAb is a novel, fully human therapeutic monoclonal antibody with high affinity for B. anthracis PA. In the rat model of inhalational anthrax, PAmAb provided complete protection against lethality when administered as a single dose [8]. In rabbit and monkey models, PAmAb improved survival rate and survival time in a statistically significant and dose-dependent manner [9, 10]. Here, we present the results of a randomized, single-blind, placebo-controlled study that was conducted with healthy human volunteers to assess the safety, pharmacokinetics, and biological activity of PAmAb.

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Patients and Methods

Basic study design. A phase 1, randomized, single-blind, placebo-controlled, dose-escalation study of PAmAb was conducted with healthy subjects. The study was designed to evaluate the safety, pharmacokinetics, and bioactivity of PAmAb at 3 intramuscular dose levels (from 0.3 to 3.0 mg/kg) and 5 intravenous dose levels (from 1.0 to 40 mg/kg). Healthy adult subjects were randomized to receive a single dose of PAmAb (ABthrax antibody; Human Genome Sciences) or a matching placebo among 10 sequential dosing cohorts. Within each of the cohorts receiving intramuscular injection (IM cohorts), 11 subjects were enrolled, with 8 subjects receiving active PAmAb and 3 subjects receiving placebo. Within each of the cohorts receiving intravenous administration (hereafter, the “IV cohorts”), 10 subjects were enrolled, with 8 subjects receiving active PAmAb and 2 subjects receiving placebo. Subjects were observed for 56 days after dosing.

This study was conducted at PAREXEL International (Baltimore, MD) in compliance with standards for good clinical practice as described in the International Conference on Harmonisation guidelines, which assures that the rights, safety, and well-being of subjects are protected in accordance with principles that have their origin in the Declaration of Helsinki. Written informed consent was obtained from each subject prior to the performance of any screening procedures.

Subjects. Healthy adult subjects (age, 18–65 years) with no history or evidence of active, significant, acute, or chronic illness were enrolled. Significant exclusionary criteria included being a pregnant or lactating woman; having had prior immunization with anthrax vaccine adsorbed (AVA; BioPort) or any investigational anthrax therapy; having a test result positive for HIV, hepatitis B surface antigen, or hepatitis C virus; or having a positive result of a urine drug screen or a current drug or alcohol addiction. Subjects were permitted to continue use of baseline oral contraceptives and over-the-counter antihistamines, vitamins, and nutritional supplements during the study.

Study agent administration. PAmAb is a recombinant, fully human, IgG1λ monoclonal antibody that binds B. anthracis PA with high affinity and inhibits its biological activity. PAmAb is expressed in the NS0 mouse myeloma cell line, secreted into culture media, and purified by a series of chromatography and filtration steps [11]. PAmAb and matching placebo were supplied as a liquid formulation and were stored in sterile, single-use vials. For intramuscular administration, the study agent was injected using a 21-gauge, 2-inch (5.1-cm) needle either in the upper-outer quadrant of the right or left gluteus maximus or in the vastus lateralis muscle in two cohorts (hereafter, the “IM-GM” and “IM-VL” cohorts, respectively). Dose levels of 0.3, 1.0, and 3.0 mg/kg were evaluated at the gluteus maximus site, and dose levels of 1.0 and 3.0 mg/kg were evaluated at the vastus lateralis site. A maximum volume of 5 mL for gluteus maximus injection and 4 mL for vastus lateralis injection was administered at a single injection site; otherwise, the dose volume was equally divided and injected at 2 sites in the appropriate muscle. For intravenous administration, study agent was diluted in normal saline and infused over a minimum period of 2 h. Dose levels of 1.0, 3.0, 10, 20, and 40 mg/kg were evaluated for intravenous administration.

Safety evaluation. Evaluation of safety included adverse-event monitoring, physical examination, and clinical laboratory assessments (i.e., hematological analysis, serum chemistry, and urinalysis). Safety was assessed from baseline prior to dosing through 56 days after dosing. The development of a serum anti-PAmAb antibody response was assessed prior to dosing and up to 56 days after dosing through immunogenicity assays based on ELISA methodology. Samples were considered positive for an anti-PAmAb antibody response if the titer in the presence of PAmAb was lower than the titer in the absence of PAmAb (P < .05, for 1-sided Z test).

Pharmacokinetics evaluation. Blood samples for pharmacokinetic analysis were collected on day 0, within 30 min prior to dosing, and at 1.5, 3, 6, and 12 h after dosing and on day 1 (24 h after dose); day 2 (48 h and 58 h after dose); day 5 (120 h after dose); and days 7, 14, 28, 42, and 56. For subjects receiving intramuscular injection, additional blood samples were obtained on days 3 and 4 (72 h and 96 h after dose, respectively). Serum concentration of PAmAb in each sample was interpolated from a PAmAb standard curve by use of ELISA-based methodologies.

Pharmacokinetic parameters were calculated using noncompartmental techniques. All pharmacokinetic analyses were conducted on uniformly weighted log-transformed data. The area under concentration-time curve (AUC) was calculated using the linear up/log down trapezoidal rule.

Quantitation of bioactivity. Blood samples for quantitation of bioactivity were collected on day 0 within 30 min prior to dosing and on days 1, 2, 5, 7, 14, 28, 42, and 56, concurrently with samples obtained for pharmacokinetics evaluation. The cyclic adenosine monophosphate (cAMP) induction bioassay was performed as described elsewhere [12]. In brief, serial dilutions of patient serum samples were incubated with a fixed concentration of PA/EF mixture to allow for antibody neutralization of PA. The serum-PA/EF mixture was added to CHO-K1 cells seeded into cAMP-Direct ELISA plates (Applied Biosystems; catalog #T-1507), and cAMP production was assayed by competitive ELISA. The mean concentration of biologically active PAmAb in each serum sample was interpolated from a PAmAb standard curve.

Statistical analyses. For safety analyses, the modified intention-to-treat (ITT) population, defined as the subset of all randomized subjects who received the study agent, was used. The modified ITT analysis was based on the planned treatment group rather than the actual treatment received. Subjects receiving placebo with each mode of administration were pooled together by mode to form 3 corresponding control groups (IM-GM, IM-VL, and IV control cohorts). Data on the occurrence of adverse events were analyzed using Fisher's exact test. The correlation between the concentration of PAmAb measured by the bioassay and the pharmacokinetics measured by ELISA was analyzed using a repeated measures analysis of variance (ANOVA). Dose linearity was evaluated using 1-way ANOVA for the IV and IM-GM cohorts and unpaired t tests for IM-VL cohorts. The effect of injection site on selected pharmacokinetic parameters was evaluated using unpaired t tests.

All statistical tests were 2-sided and were performed at a significance level of .05, unless otherwise specified. Because of the exploratory nature of this study, no adjustments for multiple data comparisons were made. All statistical analyses were performed using SAS (SAS Institute), R statistical package (The R Foundation for Statistical Computing), Prism (GraphPad Software), and WinNonlin (Pharsight) software.

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Results

Subject disposition and demographic characteristics. A total of 105 subjects in 10 cohorts were treated. Eighty subjects received PAmAb, 25 received placebo, and 102 (97%) completed the study. Notably, none of the subjects withdrew as a result of a safety concern. The 3 subjects who did not complete the study discontinued by request because the participant had a job relocation (1 subject), was lost to follow-up 2 days after study agent administration (1), or was noncompliant with the study visit schedule (1). Data for all 105 subjects were included in the analyses. The majority of subjects in this study were male (66%) and black or African American (69%) (table 1). The age range was 18–64 years, and body mass index ranged from 19.0 to 54.3. The treatment groups had similar profiles for demographic and baseline variables.

Figure 1
Figure 1

Mean serum concentrations (±SD) of PAmAb in subjects administered a single dose of 0.3, 1.0, or 3.0 mg/kg by intramuscular (IM) injection in the gluteus maximus (GM) or vastus lateralis (VL).

Figure 2
Figure 2

Mean serum concentrations (±SD) of PAmAb in subjects administered a single dose of 1.0, 3.0, 10, 20, or 40 mg/kg by intravenous (IV) infusion.

Figure 3
Figure 3

Mean serum concentrations (±SD) of PAmAb as measured by bioactivity in subjects administered a single dose of 0.3, 1.0, or 3.0 mg/kg by intramuscular (IM) injection in the gluteus maximus (GM) or vastus lateralis (VL).

Figure 4
Figure 4

Mean serum concentrations (±SD) of PAmAb as measured by bioactivity in subjects administered a single dose of 1.0, 3.0, 10, 20, or 40 mg/kg by intravenous (IV) infusion.

Table 1
Table 1

Demographic and clinical characteristics of subjects at baseline, by site and type of administration and dose of PAmAb.

Safety. In general, PAmAb was safe and well tolerated. There were no dose-limiting adverse events experienced by any subject during the study period. Most of the adverse events were transient, mild to moderate in severity, and similar in type and severity among subjects receiving placebo and subjects receiving PAmAb. There was no relation between the number of subjects with adverse events and PAmAb dose, administration route, or administration site. The most common adverse events among subjects receiving PAmAb were headache (28%), arthralgia (10%), and nausea (8%) among the IV cohorts and cough (20%), headache (10%), and rhinorrhea (8%) among the IM cohorts (table 2). Among placebo subjects, headache (24%), nasal congestion (8%), and venipuncture site pain (8%) were the most common adverse events. Overall, <15% of subjects receiving PAmAb had an adverse event that was reported to be related to the study agent. Serious adverse events of pyelonephritis and asthma 8 weeks after dosing were reported for a subject with a prior history of urinary tract infections and asthma, which was not disclosed at the time of the study.

Table 2
Table 2

Most common adverse events observed in ⩾3 subjects who received PAmAb, across all cohorts, by dose level.

Administration site adverse events were reported for subjects given PAmAb but not those given placebo. Of the 40 subjects who received PAmAb via intramuscular injection, 6 experienced an injection site reaction (table 2). Three of these 6 individuals received PAmAb, 3.0 mg/kg, the highest dose evaluated by this route, with injection volumes of 5.0 and 6.0 mL for IM-GM subjects and 4.3 mL for IM-VL subjects, administered at 1 or 2 sites in the appropriate muscle. All of the administration site adverse events were considered mild and resolved without sequelae or medical intervention.

No clinically significant hematology or clinical chemistry abnormalities were observed. thyroid-stimulating hormone (TSH) and free thyroxine levels remained within the normal range for all subjects except 1, who developed an increase in TSH levels consistent with subclinical hypothyroidism. This subject was subsequently found to have had antibodies to thyroperoxidase prior to PAmAb administration. Fluctuations in creatine phosphokinase (CPK) levels were observed for several subjects, including 3 subjects who received placebo (2 from the IV cohort and 1 from the IM cohorts), 2 subjects who received intravenous PAmAb, and 4 subjects who received intramuscular PAmAb (3 from IM-GM and 1 from IM-VL cohorts). The elevated CPK levels were not associated with clinical symptoms or elevations in levels of other liver enzymes. In many instances, these elevations were directly associated with the level of recent physical activity.

Pharmacokinetics. Serum concentrations of PAmAb were detectable in most subjects throughout the 56-day sampling period. Mean serum concentrations and pharmacokinetic parameters are presented in figure 1 and table 3 for IM cohorts and in figure 2 and table 4 for IV cohorts. The mean terminal elimination half-life ranged from 15 to 19 days for the 5 IM cohorts and from 16 to 19 days for the 5 IV cohorts. Clearance (CL/F) values were similar across doses within each route of administration. After intravenous infusion, steady-state volume ranged from 58 to 73 mL/kg, indicating that PAmAb was not confined to the plasma volume and was distributed to tissues.

Table 3
Table 3

Pharmacokinetic parameters for a single intramuscular administration of PAmAb to either the gluteus maximus (GM) or the vastus lateralis (VL).

Table 4
Table 4

Pharmacokinetic parameters for a single intravenous administration of PAmAb, by dose.

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 (table 5). Dose-normalized maximum concentration and AUC0–∞ values were significantly lower (23% and 28% lower, respectively; P < .05) for IM-GM administration than for IM-VL administration. The terminal volume of distribution was significantly (46%) larger for IM-GM cohorts. CL/F was 33% greater for IM-GM administration, but this finding was not statistically significant. Because CL/F reflects bioavailability for the 2 injection sites, PAmAb injections in the vastus lateralis appeared to be more completely absorbed than injections in the gluteus maximus. The bioavailability of PAmAb was 50%–54% for IM-GM injection and 71%–85% for IM-VL injection. For both IM-GM and IM-VL cohorts, the time to reach maximum concentration was χ6 days after intramuscular injection.

Table 5
Table 5

Comparison of pharmacokinetic parameters for 2 different sites of a single intramuscular administration of PAmAb.

cAMP induction bioassay. The levels of biologically active PAmAb, as assessed by the cAMP induction bioassay during the study period, are shown in figures 3 and 4. Similar to PAmAb serum concentrations measured in the pharmacokinetics assays, PAmAb bioactivity was detectable after a single administration for most of the subjects throughout the 56-day sampling period. With the exception of the subjects receiving a 0.3-mg/kg dose, for whom circulating levels of PAmAb approached the limits of detection for the bioassay, the slopes and half-lives measured by the bioassay and the pharmacokinetics measured by ELISA were comparable. Furthermore, there was a significant correlation between the concentration of PAmAb measured by the bioassay and the pharmacokinetics measured by ELISA for each administration route and site (each P value was <.01), strongly supporting the assumption that the PAmAb detected in the pharmacokinetics assay is biologically active.

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Discussion

In this phase I study of a novel, fully human, high-affinity monoclonal antibody against B. anthracis PA, PAmAb was shown to be safe and well tolerated when administered as a single intravenous or intramuscular dose to healthy adult subjects. The PAmAb dose range evaluated in this study was based on dose and exposure levels that provided a survival advantage in rabbit and monkey models of aerosolized anthrax spore infection [9, 10], both of which are highly reflective of inhalational anthrax disease in humans.

Single injections of PAmAb resulted in detectable serum concentrations throughout the 56-day study period in most subjects. The mean elimination half-life of 15–19 days is consistent with other fully human monoclonal antibodies. Linearity of the pharmacokinetic profile was maintained across the dose ranges evaluated for each route and site of administration, but differences were observed between the sites of intramuscular administration. PAmAb injection into the anterolateral thigh (i.e., the vastus lateralis) resulted in higher serum concentrations, greater exposure, and higher bioavailability than injection into the gluteus maximus. This could be reflective of the differences in subcutaneous fat and vascularity at the 2 injection sites. The pharmacokinetics after intravenous dosing show that a single intravenous administration of ⩾10 mg/kg can achieve serum concentrations of >100 µg/mL for ⩾7 days after administration and is still detectable (i.e., has a concentration of >1 µg/mL) on day 56. Thus, PAmAb levels were achieved in excess of anti-PA Ab levels (35–100 µg/mL) that correlated with significant survival benefit in previous animal models of vaccine [13, 14] and PAmAb [9, 10]. The cAMP-induction bioassay conducted in parallel with the pharmacokinetic samples demonstrated that biologically active PAmAb was detected across the 56-day study period in most subjects.

B. anthracis PA is the singularly pivotal antigen required for protective immunity to anthrax, and vaccination with PA provides a survival benefit in animal models, even when bacteremia is present [13, 14]. Furthermore, hyperimmune serum obtained from individuals previously vaccinated with PA (via AVA) has been shown to be protective in both in vitro and in vivo models [15, 16] and is planned for clinical study, as posted on the National Institutes of Health Web site (http://www.ClinicalTrials.gov/). Anti-PA monoclonal antibodies have several theoretical advantages over hyperimmune serum, including greater specificity, feasibility of large-scale production, and an improved safety profile. The availability of a fully human monoclonal antibody against PA that is safe, is well tolerated, has a long half-life after a single administration in humans, and provides serum concentrations that have been shown to provide protection in animal models addresses a major unmet medical need in the treatment and prevention of the pathology mediated by anthrax toxin.

Possible scenarios for the use of PAmAb include use in individuals with suspected or probable exposure to aerosolized anthrax spores. These individuals could potentially receive PAmAb with the goal of treating anthrax infection or preventing the development of clinical disease. Although antibiotics are currently recommended in this scenario, the antitoxin properties of PAmAb could play a significant role in the event of exposure to drug-resistant strains of anthrax or in cases in which antibiotics are contraindicated. In addition, PAmAb does not prevent the development of protective immunity, as shown in cynomolgus monkeys. Cynomolgus monkeys that survived initial anthrax exposure in the presence of PAmAb developed protective antibodies and survived rechallenge with anthrax spores 1 year later, with a survival rate of 100% [17]. Furthermore, PAmAb may be beneficial even when administered after the onset of shock, as shown in a rat model, in which improvements in outcome due to PAmAb were significant when it was administered up to 6 h (and approached significance when administered up to 12 h) after initial exposure to B. anthracis lethal toxin [18].

This report describes the first investigational agent against anthrax infection to be evaluated in a clinical study since the 2001 anthrax attacks in the United States. In this study of >100 healthy subjects, we have shown that PAmAb can be safely administered, is well tolerated, and is bioavailable. Further expanded safety studies with a larger number of subjects are warranted, as well as additional combination studies of PAmAb with antibiotic and vaccine agents to assess the safety of these potential combination regimens in humans.

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Acknowledgments

Financial support. Human Genome Sciences. Statistical, pharmacokinetic, and other analyses were performed by Human Genome Sciences.

Potential conflicts of interest. G.M.S., P.W.C., S.M.S., J.Z., Y.O., J.F.Z., B.L.O., and W.W.F. were employed full time by Human Genome Sciences at the time of study conduct. G.P. and A.W. are employed by PAREXEL International.

  • Received November 22, 2004.
  • Revision received February 11, 2005.
  • Accepted May 24, 2005.
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  1. Clin Infect Dis. (2005) 41 (1): 12-20. doi: 10.1086/430708
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