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

Kevin S. Thorneloe, Armin Sepp, Sean Zhang, Laura Galinanes-Garcia, Paul Galette, Wasfi Al-Azzam, Danielle J. Vugts, Guus van Dongen, Phillip Elsinga, Johan Wiegers, Andor W. J. M. Glaudemans, Veena Vincent, Jessica Renaux, Matt Szapacs, Mary Birchler, Matthew Cleveland, Mats Bergstrom, Marie Davies

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Abstract: 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.
Original languageEnglish
Article number45
JournalEJNMMI Research
Volume9
DOIs
Publication statusPublished - 2019

Cite this

Thorneloe, K. S., Sepp, A., Zhang, S., Galinanes-Garcia, L., Galette, P., Al-Azzam, W., ... Davies, M. (2019). The biodistribution and clearance of AlbudAb, a novel biopharmaceutical medicine platform, assessed via PET imaging in humans. EJNMMI Research, 9, [45]. https://doi.org/10.1186/s13550-019-0514-9
Thorneloe, Kevin S. ; Sepp, Armin ; Zhang, Sean ; Galinanes-Garcia, Laura ; Galette, Paul ; Al-Azzam, Wasfi ; Vugts, Danielle J. ; van Dongen, Guus ; Elsinga, Phillip ; Wiegers, Johan ; Glaudemans, Andor W. J. M. ; Vincent, Veena ; Renaux, Jessica ; Szapacs, Matt ; Birchler, Mary ; Cleveland, Matthew ; Bergstrom, Mats ; Davies, Marie. / The biodistribution and clearance of AlbudAb, a novel biopharmaceutical medicine platform, assessed via PET imaging in humans. In: EJNMMI Research. 2019 ; Vol. 9.
@article{a3306491a8fc4dd69adb308e466369fd,
title = "The biodistribution and clearance of AlbudAb, a novel biopharmaceutical medicine platform, assessed via PET imaging in humans",
abstract = "Abstract: 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.",
author = "Thorneloe, {Kevin S.} and Armin Sepp and Sean Zhang and Laura Galinanes-Garcia and Paul Galette and Wasfi Al-Azzam and Vugts, {Danielle J.} and {van Dongen}, Guus and Phillip Elsinga and Johan Wiegers and Glaudemans, {Andor W. J. M.} and Veena Vincent and Jessica Renaux and Matt Szapacs and Mary Birchler and Matthew Cleveland and Mats Bergstrom and Marie Davies",
year = "2019",
doi = "10.1186/s13550-019-0514-9",
language = "English",
volume = "9",
journal = "EJNMMI Research",
issn = "2191-219X",
publisher = "Springer Berlin",

}

Thorneloe, KS, Sepp, A, Zhang, S, Galinanes-Garcia, L, Galette, P, Al-Azzam, W, Vugts, DJ, van Dongen, G, Elsinga, P, Wiegers, J, Glaudemans, AWJM, Vincent, V, Renaux, J, Szapacs, M, Birchler, M, Cleveland, M, Bergstrom, M & Davies, M 2019, 'The biodistribution and clearance of AlbudAb, a novel biopharmaceutical medicine platform, assessed via PET imaging in humans' EJNMMI Research, vol. 9, 45. https://doi.org/10.1186/s13550-019-0514-9

The biodistribution and clearance of AlbudAb, a novel biopharmaceutical medicine platform, assessed via PET imaging in humans. / Thorneloe, Kevin S.; Sepp, Armin; Zhang, Sean; Galinanes-Garcia, Laura; Galette, Paul; Al-Azzam, Wasfi; Vugts, Danielle J.; van Dongen, Guus; Elsinga, Phillip; Wiegers, Johan; Glaudemans, Andor W. J. M.; Vincent, Veena; Renaux, Jessica; Szapacs, Matt; Birchler, Mary; Cleveland, Matthew; Bergstrom, Mats; Davies, Marie.

In: EJNMMI Research, Vol. 9, 45, 2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - The biodistribution and clearance of AlbudAb, a novel biopharmaceutical medicine platform, assessed via PET imaging in humans

AU - Thorneloe, Kevin S.

AU - Sepp, Armin

AU - Zhang, Sean

AU - Galinanes-Garcia, Laura

AU - Galette, Paul

AU - Al-Azzam, Wasfi

AU - Vugts, Danielle J.

AU - van Dongen, Guus

AU - Elsinga, Phillip

AU - Wiegers, Johan

AU - Glaudemans, Andor W. J. M.

AU - Vincent, Veena

AU - Renaux, Jessica

AU - Szapacs, Matt

AU - Birchler, Mary

AU - Cleveland, Matthew

AU - Bergstrom, Mats

AU - Davies, Marie

PY - 2019

Y1 - 2019

N2 - Abstract: 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.

AB - Abstract: 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.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/31115711

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DO - 10.1186/s13550-019-0514-9

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