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

EJNMMI Research

Phillip Elsinga¹  Andor W. J. M. Glaudemans¹  Johan Wiegers¹  Matthew Cleveland²  Armin Sepp²  Marie Davies²  Mats Bergstrom²  Jessica Renaux²  Laura Galinanes-Garcia²  Sean Zhang³  Matt Szapacs³  Kevin S. Thorneloe³  Wasfi Al-Azzam³  Mary Birchler³  Paul Galette³  Veena Vincent³  Guus van Dongen⁴  Danielle J. Vugts⁴ 

[1] 0000 0000 9558 4598, grid.4494.d, University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen, The Netherlands;0000 0001 2162 0389, grid.418236.a, GSK, Gunnels Wood Road, SG1 2NY, Stevenage, Herts, UK;0000 0004 0393 4335, grid.418019.5, GSK, South Collegeville Road, 19426, Collegeville, PA, USA;0000 0004 0435 165X, grid.16872.3a, VU University Medical Center, 1081 HV, Amsterdam, The Netherlands;

关键词: Domain antibody;    Albumin;    AlbudAb;    PET/CT;    Biodistribution;    Zr;   

DOI  :  10.1186/s13550-019-0514-9

来源: publisher

【 摘 要 】

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).MethodsA 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.Results89Zr-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.ConclusionEvaluating 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.

【 授权许可】

CC BY