GSK2374697, a long duration glucagon-like peptide-1 (GLP-1) receptor agonist, reduces postprandial circulating endogenous total GLP-1 and peptide YY in healthy subjects.

We investigated the effects of a long-duration glucagon-like peptide-1 (GLP-1) receptor agonist, GSK2374697, on postprandial endogenous total GLP-1 and peptide YY (PYY). Two cohorts of healthy subjects, one normal/overweight and one obese, were randomized to receive GSK2374697 2 mg (n = 8 each) or placebo (n = 4 and n = 2) subcutaneously on days 1, 4 and 7. Samples for plasma endogenous GLP-1 and PYY were collected after breakfast on days -1 and 12. Weighted mean area under the curve (0-4 h) of total GLP-1 and PYY in treated subjects was reduced compared with placebo. The least squares mean difference for change from baseline was -1.24 pmol/l [95% confidence interval (CI) -2.33, -0.16] and -4.47 pmol/l (95% CI -8.74, -0.20) for total GLP-1 and PYY, respectively, in normal/overweight subjects (p < 0.05 for both), and -1.56 (95% CI -2.95, -0.16) and -3.02 (95% CI -8.58, 2.55), respectively, in obese subjects (p < 0.05 for GLP-1). In healthy subjects, GSK2374697 reduced postprandial total GLP-1 and PYY levels, suggesting feedback suppression of enteroendocrine L-cell secretion of these peptides.

Apelin peptides linked to anti-serum albumin domain antibodies retain affinity in vitro and are efficacious receptor agonists in vivo.

The apelin receptor is a potential target in the treatment of heart failure and pulmonary arterial hypertension where levels of endogenous apelin peptides are reduced but significant receptor levels remain. Our aim was to characterise the pharmacology of a modified peptide agonist, MM202, designed to have high affinity for the apelin receptor and resistance to peptidase degradation and linked to an anti-serum albumin domain antibody (AlbudAb) to extend half-life in the blood. In competition, binding experiments in human heart MM202-AlbudAb (pKi  = 9.39 ± 0.09) bound with similar high affinity as the endogenous peptides [Pyr1 ]apelin-13 (pKi  = 8.83 ± 0.06) and apelin-17 (pKi  = 9.57 ± 0.08). [Pyr1 ]apelin-13 was tenfold more potent in the cAMP (pD2  = 9.52 ± 0.05) compared to the ß-arrestin (pD2  = 8.53 ± 0.03) assay, whereas apelin-17 (pD2  = 10.31 ± 0.28; pD2  = 10.15 ± 0.13, respectively) and MM202-AlbudAb (pD2  = 9.15 ± 0.12; pD2  = 9.26 ± 0.03, respectively) were equipotent in both assays, with MM202-AlbudAb tenfold less potent than apelin-17. MM202-AlbudAb bound to immobilised human serum albumin with high affinity (pKD  = 9.02). In anaesthetised, male Sprague Dawley rats, MM202-AlbudAb (5 nmol, n = 15) significantly reduced left ventricular systolic pressure by 6.61 ± 1.46 mm Hg and systolic arterial pressure by 14.12 ± 3.35 mm Hg and significantly increased cardiac contractility by 533 ± 170 mm Hg/s, cardiac output by 1277 ± 190 RVU/min, stroke volume by 3.09 ± 0.47 RVU and heart rate by 4.64 ± 2.24 bpm. This study demonstrates that conjugating an apelin mimetic peptide to the AlbudAb structure retains receptor and in vivo activity and may be a new strategy for development of apelin peptides as therapeutic agents.

Cross-species/cross-modality physiologically based pharmacokinetics for biologics: 89Zr-labelled albumin-binding domain antibody GSK3128349 in humans.

Two-pore physiologically-based pharmacokinetics (PBPK) for biologics describes the tissue distribution and elimination kinetics of soluble proteins as a function of their hydrodynamic radius and the physiological properties of the organs. Whilst many studies have been performed in rodents to parameterize the PBPK framework in terms of organ-specific lymph flow rates, similar validation in humans has been limited. This is mainly due to the paucity of the tissue distribution time course data for biologics that is not distorted by target-related binding. Here, we demonstrate that a PBPK model based on rodent data provided good to satisfactory extrapolation to the tissue distribution time course of 89Zr-labeled albumin-binding domain antibody (AlbudAb™) GSK3128349 in healthy human volunteers, including correct prediction of albumin-like plasma half-life, volume of distribution, and extravasation half-life. The AlbudAb™ used only binds albumin, and hence it also provides information about the tissue distribution kinetics and turnover of that ubiquitous and multifunctional plasma protein.

The biodistribution and clearance of AlbudAb, a novel biopharmaceutical medicine platform, assessed via PET imaging in humans.

Conjugation or fusion to AlbudAbs™ (albumin-binding domain antibodies) is a novel approach to extend the half-life and alter the tissue distribution of biological and small molecule therapeutics. To understand extravasation kinetics and extravascular organ concentrations of AlbudAbs in humans, we studied tissue distribution and elimination of a non-conjugated 89Zr-labeled AlbudAb in healthy volunteers using positron emission tomography/computed tomography (PET/CT). METHODS: A non-conjugated AlbudAb (GSK3128349) was radiolabeled with 89Zr and a single 1 mg (~ 15 MBq) dose intravenously administered to eight healthy males. 89Zr-AlbudAb tissue distribution was followed for up to 7 days with four whole-body PET/CT scans. 89Zr-AlbudAb tissue concentrations were quantified in organs of therapeutic significance, measuring standardized uptake value and tissue/plasma ratios. Plasma pharmacokinetics were assessed by gamma counting and LC-MS/MS of blood samples. RESULTS: 89Zr-AlbudAb administration and PET/CT procedures were well tolerated, with no drug-related immunogenicity or adverse events. 89Zr-AlbudAb rapidly distributed throughout the vasculature, with tissue/plasma ratios in the liver, lungs, and heart relatively stable over 7 days post-dose, ranging between 0.1 and 0.5. The brain tissue/plasma ratio of 0.025 suggested minimal AlbudAb blood-brain barrier penetration. Slowly increasing ratios in muscle, testis, pancreas, and spleen reflected either slow AlbudAb penetration and/or 89Zr residualization in these organs. Across all tissues evaluated, the kidney tissue/plasma ratio was highest (0.5-1.5 range) with highest concentration in the renal cortex. The terminal half-life of the 89Zr-AlbudAb was 18 days. CONCLUSION: Evaluating the biodistribution of 89Zr-AlbudAb in healthy volunteers using a low radioactivity dose was successful (total subject exposure ~ 10 mSv). Results indicated rapid formation of reversible, but stable, complexes between AlbudAb and albumin upon dosing. 89Zr-AlbudAb demonstrated albumin-like pharmacokinetics, including limited renal elimination. This novel organ-specific distribution data for AlbudAbs in humans will facilitate a better selection of drug targets to prosecute using the AlbudAb platform and significantly contribute to modeling work optimizing dosing of therapeutic AlbudAbs in the clinic.