Reproducibility of GMP-compliant production of therapeutic stressed peripheral blood mononuclear cell-derived secretomes, a novel class of biological medicinal products
Abstract Background The recent concept of secretome-based tissue regeneration has profoundly altered the field of regenerative medicine and offers promising novel therapeutic options. In contrast to medicinal products with a single active substance, cell-derived secretomes comprise pleiotropic bioac...
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doaj-8510a4803f6c4c24aea52fe3a003070b2021-01-03T12:05:04ZengBMCStem Cell Research & Therapy1757-65122020-01-0111111610.1186/s13287-019-1524-2Reproducibility of GMP-compliant production of therapeutic stressed peripheral blood mononuclear cell-derived secretomes, a novel class of biological medicinal productsMaria Laggner0Alfred Gugerell1Christiane Bachmann2Helmut Hofbauer3Vera Vorstandlechner4Marcus Seibold5Ghazaleh Gouya Lechner6Anja Peterbauer7Sibylle Madlener8Svitlana Demyanets9Dirk Sorgenfrey10Tobias Ostler11Michael Erb12Michael Mildner13Hendrik Jan Ankersmit14Division of Thoracic Surgery, Medical University of ViennaDivision of Thoracic Surgery, Medical University of ViennaIndependent ConsultantDivision of Thoracic Surgery, Medical University of ViennaDivision of Thoracic Surgery, Medical University of ViennaAposcience AGAposcience AGAustrian Red Cross Blood Transfusion Service of Upper AustriaMolecular Neuro-Oncology, Department of Pediatrics and Adolescent Medicine and Institute of Neurology, Medical University of ViennaDepartment for Laboratory Medicine at the Medical University of ViennaDr. Regenold GmbHSYNLAB Analytics and Services Switzerland AGSYNLAB Analytics and Services Switzerland AGResearch Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of ViennaDivision of Thoracic Surgery, Medical University of ViennaAbstract Background The recent concept of secretome-based tissue regeneration has profoundly altered the field of regenerative medicine and offers promising novel therapeutic options. In contrast to medicinal products with a single active substance, cell-derived secretomes comprise pleiotropic bioactive ingredients, representing a major obstacle for reproducible drug product efficacy and warranting patient safety. Good manufacturing practice (GMP)-compliant production guarantees high batch-to-batch consistency and reproducible efficacy of biological medicinal products, but different batches of cellular secretomes produced under GMP have not been compared yet, and suitable quality control parameters have not been established. To this end, we analyzed diverse biological and functional parameters of different batches produced under GMP of the secretome obtained from γ-irradiated peripheral blood mononuclear cells with proven tissue regenerative properties in infarcted myocardium, stroke, spinal cord injury, and skin wounds. Methods We quantified key secretome ingredients, including cytokines, lipids, and extracellular vesicles, and functionally assessed potency in tube formation assay, ex vivo aortic ring sprouting assay, and cell-based protein and reporter gene assays. Furthermore, we determined secretome stability in different batches after 6 months of storage at various ambient temperatures. Results We observed that inter-batch differences in the bioactive components and secretome properties were small despite considerable differences in protein concentrations and potencies between individual donor secretomes. Stability tests showed that the analytical and functional properties of the secretomes remained stable when lyophilisates were stored at temperatures up to + 5 °C for 6 months. Conclusions We are the first to demonstrate the consistent production of cell-derived, yet cell-free secretome as a biological medicinal product. The results from this study provide the basis for selecting appropriate quality control parameters for GMP-compliant production of therapeutic cell secretomes and pave the way for future clinical trials employing secretomes in tissue regenerative medicine.https://doi.org/10.1186/s13287-019-1524-2Regenerative medicineCell-free secretomesParacrine factorsSecretomeGood manufacturing practiceReproducibility |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Maria Laggner Alfred Gugerell Christiane Bachmann Helmut Hofbauer Vera Vorstandlechner Marcus Seibold Ghazaleh Gouya Lechner Anja Peterbauer Sibylle Madlener Svitlana Demyanets Dirk Sorgenfrey Tobias Ostler Michael Erb Michael Mildner Hendrik Jan Ankersmit |
spellingShingle |
Maria Laggner Alfred Gugerell Christiane Bachmann Helmut Hofbauer Vera Vorstandlechner Marcus Seibold Ghazaleh Gouya Lechner Anja Peterbauer Sibylle Madlener Svitlana Demyanets Dirk Sorgenfrey Tobias Ostler Michael Erb Michael Mildner Hendrik Jan Ankersmit Reproducibility of GMP-compliant production of therapeutic stressed peripheral blood mononuclear cell-derived secretomes, a novel class of biological medicinal products Stem Cell Research & Therapy Regenerative medicine Cell-free secretomes Paracrine factors Secretome Good manufacturing practice Reproducibility |
author_facet |
Maria Laggner Alfred Gugerell Christiane Bachmann Helmut Hofbauer Vera Vorstandlechner Marcus Seibold Ghazaleh Gouya Lechner Anja Peterbauer Sibylle Madlener Svitlana Demyanets Dirk Sorgenfrey Tobias Ostler Michael Erb Michael Mildner Hendrik Jan Ankersmit |
author_sort |
Maria Laggner |
title |
Reproducibility of GMP-compliant production of therapeutic stressed peripheral blood mononuclear cell-derived secretomes, a novel class of biological medicinal products |
title_short |
Reproducibility of GMP-compliant production of therapeutic stressed peripheral blood mononuclear cell-derived secretomes, a novel class of biological medicinal products |
title_full |
Reproducibility of GMP-compliant production of therapeutic stressed peripheral blood mononuclear cell-derived secretomes, a novel class of biological medicinal products |
title_fullStr |
Reproducibility of GMP-compliant production of therapeutic stressed peripheral blood mononuclear cell-derived secretomes, a novel class of biological medicinal products |
title_full_unstemmed |
Reproducibility of GMP-compliant production of therapeutic stressed peripheral blood mononuclear cell-derived secretomes, a novel class of biological medicinal products |
title_sort |
reproducibility of gmp-compliant production of therapeutic stressed peripheral blood mononuclear cell-derived secretomes, a novel class of biological medicinal products |
publisher |
BMC |
series |
Stem Cell Research & Therapy |
issn |
1757-6512 |
publishDate |
2020-01-01 |
description |
Abstract Background The recent concept of secretome-based tissue regeneration has profoundly altered the field of regenerative medicine and offers promising novel therapeutic options. In contrast to medicinal products with a single active substance, cell-derived secretomes comprise pleiotropic bioactive ingredients, representing a major obstacle for reproducible drug product efficacy and warranting patient safety. Good manufacturing practice (GMP)-compliant production guarantees high batch-to-batch consistency and reproducible efficacy of biological medicinal products, but different batches of cellular secretomes produced under GMP have not been compared yet, and suitable quality control parameters have not been established. To this end, we analyzed diverse biological and functional parameters of different batches produced under GMP of the secretome obtained from γ-irradiated peripheral blood mononuclear cells with proven tissue regenerative properties in infarcted myocardium, stroke, spinal cord injury, and skin wounds. Methods We quantified key secretome ingredients, including cytokines, lipids, and extracellular vesicles, and functionally assessed potency in tube formation assay, ex vivo aortic ring sprouting assay, and cell-based protein and reporter gene assays. Furthermore, we determined secretome stability in different batches after 6 months of storage at various ambient temperatures. Results We observed that inter-batch differences in the bioactive components and secretome properties were small despite considerable differences in protein concentrations and potencies between individual donor secretomes. Stability tests showed that the analytical and functional properties of the secretomes remained stable when lyophilisates were stored at temperatures up to + 5 °C for 6 months. Conclusions We are the first to demonstrate the consistent production of cell-derived, yet cell-free secretome as a biological medicinal product. The results from this study provide the basis for selecting appropriate quality control parameters for GMP-compliant production of therapeutic cell secretomes and pave the way for future clinical trials employing secretomes in tissue regenerative medicine. |
topic |
Regenerative medicine Cell-free secretomes Paracrine factors Secretome Good manufacturing practice Reproducibility |
url |
https://doi.org/10.1186/s13287-019-1524-2 |
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