Safety and pharmacokinetics of a chimerized anti-lipoteichoic acid monoclonal antibody in healthy adults

Weisman, Leonard E.; Fischer, Gerald W.; Thackray, Helen; Johnson, Karen E.; Schuman, Richard F.; Mandy, George T.; Stratton, Beth E.; Adams, Karen; Kramer, William G.; Mond, James J.

doi:10.1016/j.intimp.2009.02.008

Cited by 35 publications

(26 citation statements)

References 16 publications

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“…This was a phase 1/2, randomized, double-blind, placebo-controlled, dose escalation study assessing the safety and pharmacokinetic profile of four dose levels of pagibaximab. Based on previous studies of a neonatal monoclonal antibody to prevent infection (33), monoclonal antibodies to treat infection (1,11), pagibaximab in animal models (37; Mond, unpublished; Weisman, unpublished), neonatal suckling rat toxicity studies (Mond, unpublished), and a pagibaximab study of adults (38), the four dose levels of pagibaximab chosen for the present study were 10, 30, 60, and 90 mg/kg. Based on these in vitro and animal studies, serum pagibaximab levels of 500 g/ml were anticipated to provide protection against the broadest spectrum of CONS and S. aureus sepsis in VLBW neonates.…”

Section: Methodsmentioning

confidence: 99%

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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

Weisman

Thackray²,

Garcia‐Prats

et al. 2009

Antimicrob Agents Chemother

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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 ...

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Section: Methodsmentioning

confidence: 99%

“…dose at 3 or 10 mg per kilogram and appeared to be safe and tolerable (38). The current clinical study, the first study of pagibaximab in VLBW neonates, was intended to evaluate the safety, tolerability, and pharmacokinetics of pagibaximab in this high-risk patient population.…”

mentioning

confidence: 99%

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

Weisman

Thackray²,

Garcia‐Prats

et al. 2009

Antimicrob Agents Chemother

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“…16,17 The chimeric IgG1k, caStx2, which binds a subunit of the E. coli protein Stx2, has been administered at 10 mg/kg. 18 Two mAbs intended to treat sepsis from staphylococci are the humanized IgG1k tebifazumab, 19 which binds clumping factor A and the chimeric IgG1 pagibaximab, 20 which binds lipoteichoic acid. Both have been dosed in healthy subjects up to 20 and 10 mg/kg, respectively.…”

Section: Similar Mab Doses Have Been Used Previously In Human Studiesmentioning

confidence: 99%

“…17,19 Pagibaximab is somewhat longer at 33 days 20 and caStx2 is shorter at 8.6 d 18 The long ch-mAb7F9 elimination half-life could be a substantial improvement over many small molecule medications used to treat METH users. Because of its 18-day half-life, ch-mAb7F9 dosing should be no more frequent than every 3 weeks, which will increase compliance for motivated patients.…”

Section: Similar Mab Doses Have Been Used Previously In Human Studiesmentioning

confidence: 99%

First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers

Stevens

Henry

Owens

et al. 2014

mAbs

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This first-in-human study examined the safety and pharmacokinetics of ch-mAb7F9, an anti-methamphetamine monoclonal antibody, in healthy volunteers. Single, escalating doses of ch-mAb7F9 over the range of 0.2 to 20 mg/kg were administered to 42 subjects who were followed for 147 d. Safety was measured by physical examinations, adverse events, vital signs, electrocardiograms, and clinical laboratory testing. Serum ch-mAb7F9 concentration and immunogenicity analyses were performed. There were no serious adverse reactions or discontinuations from the study due to adverse events. No trends emerged in the frequency, relatedness, or severity of adverse events with increased dose or between active and placebo treated subjects. Ch-mAb7F9 displayed expected IgG pharmacokinetic parameters, including a half-life of 17-19 d in the 3 highest dose groups and volume of distribution of 5-6 L, suggesting the antibody is confined primarily to the vascular compartment. Four (12.5%) of the 32 subjects receiving ch-mAb7F9 were confirmed to have developed a human anti-chimeric antibody response by the end of the study; however, this response did not appear to be dose related. Overall, no apparent safety or tolerability concerns were identified; a maximum tolerated dose was not reached in this Phase 1 study. Ch-mAb7F9 therefore appears safe for human administration.

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“…The difficulty of treatment and the slowed progress in the identification of new antibiotics necessitate the development of new approaches to antibacterial prophylaxis and therapy (29,32). One alternate strategy being explored is the use of monoclonal antibodies (MAbs) directed against a surface determinant on the pathogen and/or virulence factors produced by the invading pathogen to be used in prophylaxis or as adjunctive therapy with antibiotics (13,14,22,30,36). Antigens for which there are promising preclinical data on the use of MAbs against S. aureus include IsaA, IsdB, ClfA, and alpha toxin (AT).…”

mentioning

confidence: 99%

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

Tkaczyk¹,

Liu²,

Varkey³

et al. 2012

Clin. Vaccine Immunol.

109

140

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Safety and pharmacokinetics of a chimerized anti-lipoteichoic acid monoclonal antibody in healthy adults

Cited by 35 publications

References 16 publications

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

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

First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers

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

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