Dataset Information

Investigation of the mechanism of clearance of AMG 386, a selective angiopoietin-1/2 neutralizing peptibody, in splenectomized, nephrectomized, and FcRn knockout rodent models.

ABSTRACT:

Purpose

To investigate the mechanisms of clearance of AMG 386, an investigational recombinant peptide-Fc fusion protein (peptibody) that blocks tumor angiogenesis by neutralizing the interaction between angiopoietin-1 and -2 and the Tie2 receptor.

Methods

The role of the neonatal Fc receptor (FcRn) in AMG 386 clearance was assessed in wild-type and FcRn-knockout mice; the roles of the spleen and kidneys were assessed in splenectomized and 5/6th nephrectomized rats, respectively, compared with sham-operated rats. Animals were administered AMG 386 as a single intravenous dose of 3 or 10 mg/kg. Blood samples for pharmacokinetic analysis were collected periodically throughout a 504-hour postdose period.

Results

Compared with wild-type mice, AMG 386 clearance in FcRn-knockout mice was 18-fold faster at the 3-mg/kg dose (FcRn knockout, 13.2 mL/h/kg; wild-type, 0.728 mL/h/kg) and 14-fold faster at the 10-mg/kg dose (FcRn knockout, 10.7 mL/h/kg; wild-type, 0.777 mL/h/kg). Clearance in nephrectomized rats was slower than in sham-operated rats at both the 3-mg/kg dose (nephrectomized, 1.23 mL/h/kg; sham-operated, 1.75 mL/h/kg) and the 10-mg/kg dose (nephrectomized, 1.14 mL/h/kg; sham-operated, 1.65 mL/h/kg). Splenectomy had no apparent effect on the pharmacokinetics of AMG 386.

Conclusions

The FcRn is integral to maintaining circulating levels of AMG 386 in mice. Renal clearance contributed approximately 30% to total AMG 386 clearance in rats.

SUBMITTER: Wu B

PROVIDER: S-EPMC3296951 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Publications

Investigation of the mechanism of clearance of AMG 386, a selective angiopoietin-1/2 neutralizing peptibody, in splenectomized, nephrectomized, and FcRn knockout rodent models.

Wu Benjamin B Johnson Jessica J Soto Marcus M Ponce Manuel M Calamba Dominador D Sun Yu-Nien YN

Pharmaceutical research 20111222 4

<h4>Purpose</h4>To investigate the mechanisms of clearance of AMG 386, an investigational recombinant peptide-Fc fusion protein (peptibody) that blocks tumor angiogenesis by neutralizing the interaction between angiopoietin-1 and -2 and the Tie2 receptor.<h4>Methods</h4>The role of the neonatal Fc receptor (FcRn) in AMG 386 clearance was assessed in wild-type and FcRn-knockout mice; the roles of the spleen and kidneys were assessed in splenectomized and 5/6th nephrectomized rats, respectively, c ...[more]

PMID: 22189693

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Project description:IntroductionBlisibimod is a potent B cell-activating factor (BAFF) antagonist that binds to both cell membrane-expressed and soluble BAFF. The goal of these first-in-human studies was to characterize the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of blisibimod in subjects with systemic lupus erythematosus (SLE).MethodsSLE subjects with mild disease that was stable/inactive at baseline received either a single dose of blisibimod (0.1, 0.3, 1, or 3 mg/kg subcutaneous [SC] or 1, 3, or 6 mg/kg intravenous [IV]) or placebo (phase 1a; N = 54), or four weekly doses of blisibimod (0.3, 1, or 3 mg/kg SC or 6 mg/kg IV) or placebo (phase 1b; N = 63). Safety and tolerability measures were collected, and B cell subset measurements and pharmacokinetic analyses were performed.ResultsAll subjects (93 % female; mean age 43.7 years) carried the diagnosis of SLE for ≥ 1 year. Single- and multiple-dose treatment with blisibimod produced a decrease in the number of naïve B cells (24-76 %) and a transient relative increase in the memory B cell compartment, with the greatest effect on IgD(-)CD27+; there were no notable changes in T cells or natural killer cells. With time, memory B cells reverted to baseline, leading to a calculated 30 % reduction in total B cells by approximately 160 days after the first dose. In both the single- and multiple-dosing SC cohorts, the pharmacokinetic profile indicated slow absorption, dose-proportional exposure from 0.3 through 3.0 mg/kg SC and 1 through 6 mg/kg IV, linear pharmacokinetics across the dose range of 1.0-6.0 mg/kg, and accumulation ratios ranging from 2.21 to 2.76. The relative increase in memory B cells was not associated with safety signals, and the incidence of adverse events, anti-blisibimod antibodies, and clinical laboratory abnormalities were comparable between blisibimod- and placebo-treated subjects.ConclusionsBlisibimod changed the constituency of the B cell pool and single and multiple doses of blisibimod exhibited approximate dose-proportional pharmacokinetics across the dose range 1.0-6.0 mg/kg. The safety and tolerability profile of blisibimod in SLE was comparable with that of placebo. These findings support further studies of blisibimod in SLE and other B cell-mediated diseases.Trial registrationClinicaltrials.gov NCT02443506 . Registered 11 May 2015. NCT02411136 Registered 7 April 2015.

Dataset Information

Investigation of the mechanism of clearance of AMG 386, a selective angiopoietin-1/2 neutralizing peptibody, in splenectomized, nephrectomized, and FcRn knockout rodent models.

Purpose

Methods

Results

Conclusions

Publications

Investigation of the mechanism of clearance of AMG 386, a selective angiopoietin-1/2 neutralizing peptibody, in splenectomized, nephrectomized, and FcRn knockout rodent models.

Similar Datasets

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