Phase 1/2 Double-Blind, Placebo-Controlled, Dose Escalation, Safety, and Pharmacokinetic Study of Pagibaximab (BSYX-A110), an Antistaphylococcal Monoclonal Antibody for the Prevention of Staphylococcal Bloodstream Infections, in Very-Low-Birth-Weight Neonates

Abstract

Staphylococcal sepsis is a major cause of morbidity and mortality in very-low-birth-weight (VLBW) infants.A human chimeric monoclonal antibody, pagibaximab, was developed against staphylococcal lipoteichoic acid. We evaluated the safety, tolerability, and pharmacokinetics of pagibaximab in VLBW neonates. A phase 1/2, randomized, double-blind, placebo-controlled, dose escalation study was conducted in VLBW infants (700 to 1,300 g) 3 to 7 days old. Patients received two doses 14 days apart of intravenous pagibaximab (10, 30, 60, or 90 mg/kg of body weight) or placebo in a 2:1 ratio. Blood and urine samples were obtained pre-and postinfusion for analysis of safety and pharmacokinetics, and data on adverse events were gathered. Staphylococcal organisms causing sepsis were collected and evaluated. Fifty-three patients received at least one dose of pagibaximab or placebo. The average gestational age was 27.6 weeks; the average birth weight was 1,003 g. All serious adverse events were deemed unrelated or probably not drug related. Morbidity and mortality were similar across treatment groups. No evidence of immunogenicity of pagibaximab was detected. Pagibaximab pharmacokinetics was linear. The mean clearance (CL), volume of distribution, and elimination half-life of pagibaximab were independent of dose. The serum half-life was 20.5 ؎ 6.8 days. Pagibaximab enhanced serum opsonophagocytic activity. All staphylococci causing sepsis were opsonizable by pagibaximab. Two infusions of pagibaximab, administered 2 weeks apart to high-risk neonates appeared safe and tolerable, and pharmacokinetics were linear. Evaluation of more frequent doses, at the highest doses tested, in neonates at high-risk of staphylococcal sepsis, is warranted.Very-low-birth-weight (VLBW) neonates (Ͻ1,500-g birth weight) are at high risk for late-onset (Ͼ72 h of life) hospitalacquired sepsis (13,16,17). Such infections are a major cause of morbidity, prolong time in the hospital and intensive care unit, increase the need for antibiotics, and further increase the substantial cost of medical care for these infants (8, 17). Staphylococci, including coagulase-negative staphylococci (CONS) and Staphylococcus aureus, are responsible for between 56 and Ͼ75% of hospital-acquired, late-onset neonatal sepsis (13, 31). Recent reports (12,28,30) show continuing increases in resistance of staphylococci to antimicrobial agents. Frequent and prolonged exposures to antimicrobials have been demonstrated to increase the risk of developing infections with resistant organisms (30,34). Therapeutic products and strategies that could prevent infections would minimize the need for antimicrobial products (20).Lipoteichoic acid (LTA) is a highly conserved epitope in the staphylococcal cell wall that inhibits phagocytosis of bacteria in vitro, induces the cytokine cascade through stimulation of Tolllike receptors, and may be necessary for staphylococcal survival (18, 19, 24, 27). An anti-LTA murine/human chimeric monoclonal antibody, pagibaximab, was developed by recombinant DNA ...

Identification of Anti-Alpha Toxin Monoclonal Antibodies That Reduce the Severity of Staphylococcus aureus Dermonecrosis and Exhibit a Correlation between Affinity and Potency

“…Although there is only one anti-infective MAb currently approved for use in humans, there are other MAbs targeting pathogens being tested in human clinical trials (21,23,25,37). These anti-infective MAbs, which are specific for pathogen and not human antigens, are anticipated to have relatively few off-target toxicities.…”

Antibodies to watch in 2010

“…In a pilot study, the dose of radioactivity delivered was patient-specific, and designed to achieve a 44-Gy boost to the 2-cm SCRC margin in adult patients with newly diagnosed malignant gliomas. 29 Patients were further treated with external beam radiotherapy (55)(56)(57)(58)(59)(60) Gy approximately one month after administration of I-131 81C6) and chemotherapy (temozolomide, lomustine, irinotecan and etoposide administered in a serial manner) for 10-12 months. The study regimen was well-tolerated, and median OS for patients with glioblastoma multiforme was 90.6 weeks after a median follow-up time of 151 weeks.…”

“…In preclinical studies, pagibaximab administered at a dose of 80 mg/kg significantly increased survival of suckling rats with sepsis caused by coagulase-negative staphylococci (CoNS), and significantly increased survival in a lethal suckling rat model of Staphylococcus aureus sepsis. 56 The safety and pharmacokinetics of pagibaximab were first assessed in eight healthy subjects in 2001. 57 Adults (18 years or older) subjects were administered a single iv dose of either 3 or 10 mg/kg pagibaximab.…”

“…Pagibaximab was then evaluated in a placebo-controlled, dose escalation Phase 1/2 study in VLBW neonates. 56 Patients were administered two doses of 10, 30, 60 or 90 mg/kg iv pagibaximab, with doses administered 2 weeks apart, or placebo. Serum half-life was 20.5 days +/-6.8 days; no evidence of immunogenicity was detected.…”

Does IVIg administration yield improved immune function in very premature neonates?

“…11 A new humanized mouse chimeric monoclonal antibody directed against Staphyloccocal lipotechoic acid (a major component of the bacterial cell wall) as a means of sepsis prophylaxis is currently in phase II trials. 12 Multiple reasons have been suggested for the limited efficacy of IVIg for prevention or treatment of neonatal sepsis and include limitations in study design, insufficient dosing, variation in pathogens, low levels of neonatal pathogen-specific antibodies and use of non-IgM-enriched products. 9 An additional explanation for the lack of efficacy of IVIg may be the immature immune function of very premature neonates.…”