scholarly journals Safety, Tolerability, and Pharmacokinetics of MEDI4893, an Investigational, Extended-Half-Life, Anti-Staphylococcus aureus Alpha-Toxin Human Monoclonal Antibody, in Healthy Adults

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Xiang-Qing Yu ◽  
Gabriel J. Robbie ◽  
Yuling Wu ◽  
Mark T. Esser ◽  
Kathryn Jensen ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Monoclonal Antibody ◽  
Half Life ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Healthy Adults ◽  
Alpha Toxin ◽  
Dose Escalation Study ◽  
Content Type ◽  
Neutralizing Activity

ABSTRACT MEDI4893 is an investigational immunoglobulin G1(κ) monoclonal antibody that specifically binds to and neutralizes alpha-toxin, a key Staphylococcus aureus virulence factor. A triple-amino-acid substitution, M252Y/S254T/T256E, was engineered into the MEDI4893 Fc region to extend its serum half-life. A phase 1, double-blind, dose escalation study was designed to evaluate the safety, tolerability, pharmacokinetics, anti-alpha-toxin-neutralizing activity, and antidrug antibody (ADA) response of MEDI4893 following a single intravenous infusion in healthy adults 18 to 65 years of age. Thirty-three subjects were randomly assigned to receive MEDI4893 at 225 mg (n = 3), 750 mg (n = 3), 2,250 mg (n = 8), or 5,000 mg (n = 12) or placebo (n = 7) and were followed for 360 days. Adverse events were mild or moderate in severity; none were serious. The MEDI4893 peak serum concentration increased dose proportionally from 77.2 μg/ml (225-mg dose) to 1,784 μg/ml (5,000-mg dose). The area under the concentration-time curve from 0 to 360 days also increased dose proportionally, from 4,840 μg · day/ml (225-mg dose) to 91,493 μg · day/ml (5,000-mg dose), indicating linear pharmacokinetics. MEDI4893's terminal half-life was estimated to be 80 to 112 days, which is approximately 4-fold longer than the half-lives of other human immunoglobulin G antibodies. The alpha-toxin-neutralizing activity in serum correlated highly with the MEDI4893 concentrations in serum. Three adults transiently tested positive for ADA on day 151, but this did not have an impact on MEDI4893 serum concentrations or the MEDI4893 safety profile; no subjects exhibited serum ADA at the study end. These data support the continued development of MEDI4893 for the prevention of S. aureus-mediated pneumonia. (This study has been registered at ClinicalTrials.gov under identifier NCT02296320.)

scholarly journals 1557. Population Pharmacokinetics of Suvratoxumab (MEDI4893), an Extended Half-life Staphylococcus aureus Alpha Toxin-Neutralizing Human Monoclonal Antibody, in Healthy Adults and Patients on Mechanical Ventilation in Intensive Care Units

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S568-S569
Author(s):  
Vadryn Pierre ◽  
Bruno Francois ◽  
Martha Hernandez-Illas ◽  
Miguel Sánchez Garcia ◽  
Yuling Wu ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Monoclonal Antibody ◽  
Mechanical Ventilation ◽  
Healthy Volunteers ◽  
Population Pharmacokinetics ◽  
Half Life ◽  
Human Monoclonal Antibody ◽  
Healthy Adults ◽  
Alpha Toxin ◽  
Post Dose

Abstract Background Suvratoxumab (suvra), an extended half-life (~80 days), Staphylococcus aureus (SA) alpha toxin-neutralizing IgG monoclonal antibody, is under investigation for prevention of SA pneumonia in patients on mechanical ventilation (MV). We characterized the serum PK of suvra using population pharmacokinetics (popPK) in both healthy volunteers and MV patients and quantified the proportion of patients reaching the serum target of 211 μg/mL at 30 days post-dose. Methods The popPK analysis included 1,368 serum samples from two early phase studies (NCT02296320; EudraCT 2014-001097-34): (1) Phase 1 study in 26 healthy adults receiving single IV suvra doses ranging from 0.225g to 5g, with PK sampled up to 360 days; and (2) Phase 2 study in MV patients with PCR-confirmed SA colonization of lower respiratory tract receiving one suvra IV dose of 2g (n = 15) or 5g (n = 96), with PK sampled up to 100 days. Results A two-compartment linear model with weight-based scaling of the PK parameters adequately described the serum PK data (Figure 1). MV status, number of days on MV, and age impacted the PK of suvra. A moderate between-subject variability (<45% CV) was estimated for key PK parameters. An estimated two-fold increase in MV patients’ volume of distribution parameters compared with healthy volunteers explained the observed Cmax differences between the two groups (1145±369 μg/mL vs. 1783±396 μg/mL) (Figures 2 and 3). Although age, MV status and days on MV post-dose appeared to be associated with higher systemic clearance (CL) in the model, this estimate could be biased due to limited PK data available for only one half-life (~90 days) of the drug in MV patients (Figure 2). More patients achieved suvra levels above the PK target following the 5 g (73.5%; 50/68) vs. 2 g dose (7.6%; 1/13) at 30 days post-dose. Conclusion MV status, post-dose duration on MV, body weight, and age were identified as statistically significant covariates influencing the PK of suvra. Serum PK and popPK analyses support the 5g dose for future studies with suvra in MV patients. Disclosures All authors: No reported disclosures.

scholarly journals Epithelial Lining Fluid and Plasma Concentrations of Dalbavancin in Healthy Adults after a Single 1,500-Milligram Infusion

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Urania Rappo ◽  
Michael W. Dunne ◽  
Sailaja Puttagunta ◽  
James S. Baldassarre ◽  
Shengfang Su ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pneumoniae ◽  
Half Life ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Healthy Adults ◽  
Epithelial Lining ◽  
Phase 1 Study ◽  
Epithelial Lining Fluid ◽  
Content Type

ABSTRACT Dalbavancin is a lipoglycopeptide antibiotic with a prolonged half-life. A phase 1 study assessed dalbavancin levels in epithelial lining fluid (ELF) in 35 healthy adults using ELF bronchial microsampling up to 168 h after administration of 1,500 mg dalbavancin. The penetration of dalbavancin into ELF was 36%. ELF levels of dalbavancin exceeded the MIC90s of Streptococcus pneumoniae and Staphylococcus aureus for ≥7 days.

scholarly journals Phase 1 Randomized, Double-Blind, Placebo-Controlled Study of RG7667, an Anticytomegalovirus Combination Monoclonal Antibody Therapy, in Healthy Adults

2015 ◽  
Vol 59 (8) ◽  
pp. 4919-4929 ◽  
Author(s):  
Julie H. Ishida ◽  
Tracy Burgess ◽  
Michael A. Derby ◽  
Pearline A. Brown ◽  
Mauricio Maia ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Adverse Events ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Healthy Adults ◽  
Host Cells ◽  
Controlled Study ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Double Blind Placebo

ABSTRACTCytomegalovirus can cause debilitating and life-threatening disease in newborns infectedin uteroand immunocompromised individuals, including transplant recipients. RG7667 is a unique combination of two monoclonal antibodies that binds glycoprotein complexes on the surface of cytomegalovirus and inhibits its entry into host cells. A phase 1 first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study of RG7667 given intravenously was conducted in 181 healthy adults. The study involved a single ascending dose stage (1, 3, 5, and 10 mg/kg each antibody;n= 21), a multiple ascending dose stage (5 and 10 mg/kg each antibody monthly for 3 doses;n= 10), and a multiple dose expansion stage (10 mg/kg each antibody monthly for 3 doses;n= 150). Subjects were followed for 85 to 141 days to evaluate safety, tolerability, pharmacokinetics, and immunogenicity. Most adverse events were mild, and the incidence of adverse events was similar among the RG7667 and placebo groups. RG7667 had dose-proportional pharmacokinetics in all three dosing stages, a mean terminal half-life of 20 to 30 days, and an overall pharmacokinetic profile consistent with that of a human monoclonal antibody that lacks endogenous host targets. The proportion of subjects developing an antitherapeutic antibody response was not higher in the RG7667 group than in the placebo group. In summary, single and multiple doses of RG7667 were found to be safe and well-tolerated in healthy adults and had a favorable pharmacokinetic and immunogenicity profile. This study supports further development of RG7667 as a therapy for the prevention and treatment of cytomegalovirus infection in susceptible populations. (This study has been registered at ClinicalTrials.gov under registration no. NCT01496755.)

Phase I Clinical Trial of a Novel, Long-Acting Antithrombotic Drug: A Human Monoclonal Antibody Partially Inhibiting FVIII Activity.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 312-312 ◽  
Author(s):  
Peter Verhamme ◽  
Steve Pakola ◽  
Marc Jacquemin ◽  
Jean Marie Saint-Remy ◽  
Jean Marie Stassen ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Half Life ◽  
Human Monoclonal Antibody ◽  
Older Age ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Age Cohorts ◽  
Pharmacodynamic Profile

Abstract Current treatments for preventing thrombotic disease are still inconvenient and associated with a high risk of bleeding. Improved anticoagulant agents are therefore required. TB-402 is a monoclonal antibody (fully human IgG4-antibody) that targets factor VIII (FVIII) and represents a novel type of anticoagulant agent. In vitro, TB-402 only partially inhibits human FVIII even when TB-402 is in excess over FVIII. Preclinical studies confirmed this plateau inhibition and also established the antithrombotic efficacy of TB-402 (Jacquemin M, et al. J Thromb Haemost.2006; 4:1047). Plateau inhibition even in setting of excess TB-402 may allow for improved safety with decreased risk of overdose and decreased need for monitoring. The long half-life of the antibody creates the possibility for a once a month administration. TB-402 may therefore represent a safer and more convenient agent than other available anticoagulants. A Phase I study has completed enrolment of 56 healthy male volunteers. This randomised, double-blind, placebo-controlled, single dose, dose escalation study evaluated the safety and the pharmacokinetic/pharmacodynamic profile of TB-402. Volunteers were treated with a single intravenous administration of placebo or TB-402 at doses of 0.015, 0.1, 0.5, 2.5, 12.5, 37.5, 188, 620 or 1,860 μg/kg. All doses were evaluated in 18–45 year old volunteers, with the highest dose also evaluated in an older age, 55–75 years, cohort. Study drug has been well tolerated in both the young and the older age cohorts, with no safety issues observed. A plateau effect in terms of FVIII level inhibition has been observed. At plateau, FVIII levels were generally decreased by 1/3 to 2/3 from baseline. aPTT prolongation (generally 1.1–1.2 times baseline) was also observed whereas the Prothrombin time (PT) was not modified. aPTT prolongations at doses of ≥ 620 μg/kg were generally maintained for at least 4 weeks. Long half-life of drug and associated anticoagulant effect are supported by the finding of consistent and prolonged effect on aPTT. In conclusion, this study demonstrates that in healthy young and older volunteers a single administration of TB-402 results in a prolonged anticoagulation effect without the risk of overdosing or spontaneous hemorrhage. TB-402 will next be evaluated in patients at risk for venous thromboembolism.

A human monoclonal antibody with the capacity to neutralize Staphylococcus aureus alpha-toxin

1994 ◽  
Vol 5 (1-2) ◽  
pp. 18-24 ◽  
Author(s):  
Nikolaus Heveker ◽  
Arne Hansen ◽  
Klaus-Dieter Hungerer ◽  
Rüdiger von Baehr ◽  
Ralf W. Glaser
Keyword(s):  
Staphylococcus Aureus ◽  
Monoclonal Antibody ◽  
Human Monoclonal Antibody ◽  
Alpha Toxin

scholarly journals Anti-Alpha-Toxin Monoclonal Antibody and Antibiotic Combination Therapy Improves Disease Outcome and Accelerates Healing in a Staphylococcus aureus Dermonecrosis Model

2014 ◽  
Vol 59 (1) ◽  
pp. 299-309 ◽  
Author(s):  
Jamese J. Hilliard ◽  
Vivekananda Datta ◽  
Christine Tkaczyk ◽  
Melissa Hamilton ◽  
Agnieszka Sadowska ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Monoclonal Antibody ◽  
Soft Tissue ◽  
Single Agent ◽  
Alpha Toxin ◽  
Tissue Necrosis ◽  
Content Type ◽  
Infection Models ◽  
Neutralizing Monoclonal Antibody ◽  
Treatment Window

ABSTRACTAlpha-toxin (AT) is a major virulence determinant inStaphylococcus aureusskin and soft tissue infection models. We previously demonstrated that prophylactic administration of 2A3, an AT-neutralizing monoclonal antibody (MAb), preventsS. aureusdisease in a mouse dermonecrosis model by neutralizing AT-mediated tissue necrosis and immune evasion. In the present study, MEDI4893*, an affinity-optimized version of 2A3, was characterized for therapeutic activity in the dermonecrosis model as a single agent and in combination with two frontline antibiotics, vancomycin and linezolid. MEDI4893* postinfection therapy was found to exhibit a therapeutic treatment window similar to that for linezolid but longer than that for vancomycin. Additionally, when combined with either vancomycin or linezolid, MEDI4893* resulted in reduced tissue damage, increased neutrophil and macrophage infiltration and abscess formation, and accelerated healing relative to those with the antibiotic monotherapies. These data suggest that AT neutralization with a potent MAb holds promise for both prophylaxis and adjunctive therapy with antibiotics and may be a valuable addition to currently available options for the treatment ofS. aureusskin and soft tissue infections.

scholarly journals Staphylococcus aureus Alpha-Toxin Is Conserved among Diverse Hospital Respiratory Isolates Collected from a Global Surveillance Study and Is Neutralized by Monoclonal Antibody MEDI4893

2016 ◽  
Vol 60 (9) ◽  
pp. 5312-5321 ◽  
Author(s):  
David E. Tabor ◽  
Li Yu ◽  
Hoyin Mok ◽  
Christine Tkaczyk ◽  
Bret R. Sellman ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Monoclonal Antibody ◽  
Vaccine Development ◽  
Geographic Location ◽  
The United States ◽  
Geographic Region ◽  
Alpha Toxin ◽  
Content Type ◽  
Gene Sequence Analysis ◽  
The Subject

ABSTRACTStaphylococcus aureusinfections lead to an array of illnesses ranging from mild skin infections to serious diseases, such endocarditis, osteomyelitis, and pneumonia. Alpha-toxin (Hla) is a pore-forming toxin, encoded by thehlagene, that is thought to play a key role inS. aureuspathogenesis. A monoclonal antibody targeting Hla, MEDI4893, is in clinical development for the prevention ofS. aureusventilator-associated pneumonia (VAP). The presence of thehlagene and Hla protein in 994 respiratory isolates collected from patients in 34 countries in Asia, Europe, the United States, Latin America, the Middle East, Africa, and Australia was determined. Hla levels were correlated with the geographic location, age of the subject, and length of stay in the hospital.hlagene sequence analysis was performed, and mutations were mapped to the Hla crystal structure.S. aureussupernatants containing Hla variants were tested for susceptibility or resistance to MEDI4893. Thehlagene was present and Hla was expressed in 99.0% and 83.2% of the isolates, respectively, regardless of geographic region, hospital locale, or age of the subject. More methicillin-susceptible than methicillin-resistant isolates expressed Hla (86.9% versus 78.8%;P= 0.0007), andS. aureusisolates from pediatric patients expressed the largest amounts of Hla. Fifty-seven different Hla subtypes were identified, and 91% of the isolates encoded an Hla subtype that was neutralized by MED4893. This study demonstrates that Hla is conserved in diverseS. aureusisolates from around the world and is an attractive target for prophylactic monoclonal antibody (MAb) or vaccine development.

scholarly journals Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: A Phase 1 open-label clinical trial in healthy adults

PLoS Medicine ◽  
2018 ◽  
Vol 15 (1) ◽  
pp. e1002493 ◽  
Author(s):  
Martin R. Gaudinski ◽  
Emily E. Coates ◽  
Katherine V. Houser ◽  
Grace L. Chen ◽  
Galina Yamshchikov ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Monoclonal Antibody ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Healthy Adults ◽  
Open Label ◽  
Hiv 1

Interim results from a first-in-human study with AMG102, a fully human monoclonal antibody that neutralizes hepatocyte growth factor (HGF), the ligand to c-Met receptor, in patients (pts) with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3551-3551 ◽  
Author(s):  
M. S. Gordon ◽  
D. S. Mendelson ◽  
C. Sweeney ◽  
N. Erbeck ◽  
R. Patel ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Solid Tumors ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Dose Range ◽  
Human Study ◽  
Advanced Solid Tumors ◽  
Met Receptor ◽  
Dose Escalation Study ◽  
Grade 3

3551 Background: AMG102 is a fully human IgG2 monoclonal antibody against HGF that prevents tumorigenesis in preclinical models through blockade of the HGF/c-Met receptor tyrosine kinase pathway. We describe interim results from the first-in-human study of AMG102. Methods: This ongoing phase 1, open-label, dose-escalation study is evaluating safety, pharmacokinetics (PK), and preliminary pharmacodynamics (PD) of AMG102 after single and multiple intravenous doses in pts with advanced solid tumors. Sequential dose cohorts of 4–6 pts were administered AMG102 at 0.5, 1, 3, 5, 10, or 20 mg/kg. Pts received a single dose, followed by a 4-wk treatment- free period during which safety and PK were assessed. If no dose-limiting toxicity (DLT) was observed, treatment was resumed every 2 wks at the same dose until pts exhibited drug intolerance or disease progression. Results: As of 10 August 2006, 31 pts have been treated with AMG102 at doses up to 20 mg/kg ( Table ). AMG102 appears to be well tolerated. One pt with non-small cell lung cancer had a grade 3 DLT of dyspnea/hypoxia after the first dose (0.5 mg/kg); a second pt with pancreatic cancer had a grade 3 DLT/serious adverse event of gastrointestinal hemorrhage after the first dose (1 mg/kg). The most frequently reported, treatment-related adverse events (AEs) have been fatigue (13%), constipation (10%), anorexia (6%), nausea (6%), and vomiting (6%). No anti-AMG102 antibodies have been detected. Initial PK analysis indicates approximately linear PK in the dose range of 0.5 to 20 mg/kg. The overall mean (SD) [median] clearance and half-life estimates based on day-1 dosing were 12.1 (5.21) [10.7] mL/hr and 15.4 (5.84) [15.5] days, respectively. Tumor response is described ( Table ). Conclusions: In this study, interim results suggest that AMG102 at doses up to 20 mg/kg appears to be well-tolerated, with preliminary PK data supporting every-2-wk administration. [Table: see text] No significant financial relationships to disclose.

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