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Advances in Experimental Medicine and Biology 1420
JorgeS.BurnsEditor
Potency Assays forAdvanced Stem Cell Therapy Medicinal Products
Volume 1420
Series Editor
WimE.Crusio, Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, CNRS and University of Bordeaux, Pessac Cedex,France HaidongDong, Departments of Urology and Immunology,Mayo Clinic, Rochester,MN,USA HeinfriedH.Radeke, Institute of Pharmacology and Toxicology, Clinic of the Goethe University Frankfurt Main, Frankfurt am Main,Hessen,Germany NimaRezaei, Research Center for Immunodeciencies, Children’s Medical Center,Tehran University of Medical Sciences, Tehran,Iran OrtrudSteinlein, Institute of Human Genetics, LMU University Hospital,Munich,Germany JunjieXiao, Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences,School of Life Science, Shanghai University,Shanghai,China
Advances in Experimental Medicine and Biology provides a platform for scientic contributions in the main disciplines of the biomedicine and the life sciences. is series publishes thematic volumes on contemporary research in the areas of microbiology, immunology, neurosciences, biochemistry, biomedical engineering, genetics, physiology, and cancer research. Covering emerging topics and techniques in basic and clinical science, it brings together clinicians and researchers from various elds.
Advances in Experimental Medicine and Biology has been publishing exceptional works in the eld for over 40 years, and is indexed in SCOPUS, Medline (PubMed), EMBASE, BIOSIS, Reaxys, EMBiology, the Chemical Abstracts Service (CAS), and Pathway Studio.
2021 Impact Factor: 3.650 (no longer indexed in SCIE as of 2022)
Jorge S. Burns
Editor
Potency Assays for Advanced Stem Cell Therapy Medicinal Products
Editor
Jorge S. Burns University of Ferrara Ferrara, Italy
ISSN 0065-2598 ISSN 2214-8019 (electronic) Advances in Experimental Medicine and Biology ISBN 978-3-031-30039-4 ISBN 978-3-031-30040-0 (eBook)
https://doi.org/10.1007/978-3-031-30040-0
© Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microlms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specic statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional afliations.
This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
In memoriam Paolo Bianco (1955–2015) Luc Sensebé (1953–2020)
Preface
The potency assay serves as a hub where academic biological insights inter­twine with industrial processing knowledge, and the chapters of this book pivot on this busy juncture. Experienced contributors from academia, clinical research centres and industry provide detailed reections on the topic and are thanked enormously for having done so despite the extraordinary challenges presented by the Covid-19 pandemic.
The editor’s rst chapter draws fromthe history of the early phases of vac­cine discovery and current implementation, to highlight the sometimes­similar convoluted aspects found in the art of stem cell therapy. Risk-based therapy progressed to ethically sound effective intervention with the discov­ery of the mechanisms of action. Potency assays underscore this principle and form a vital part of the medical revolution being presented by new advanced therapy medicinal products.
The industrial sector has played a large part in driving pragmaticprogress to overcome cell-based therapy obstacles.Whilst head of research and devel­opment at Innovacell AG, Marco Thurner and his team, including Raffaela Torggler, Eva Margreiter and Rainer Marksteiner, co-contributors of Chap. 2, investigated potency assay development for clinical use. Marco led develop­ment of a potency assay for human skeletal muscle-derived cells during clini­cal phase drug development and as a prerequisite to market approval application (MAA). Measurement of the activity of acetylcholinesterase (AChE), expressed throughout skeletal and nervous tissue, was successfully elaborated as a potential potency assay for human skeletal muscle-derived cells (aSMDC) that are used to treat patients with fecal incontinence.
The research team of Joaquim Vives at the largest research teaching hospi­tal in Catalonia explores application of human multipotent stromal cells (hMSC) and the optimisation of potency assays to assess the immunomodula­tive potential of clinical-grade hMSC.Co-authored with Sílvia Torrents and Marta Grau-Vorster, Chap. 3 provides an overview to the many diverse and challenging aspects facing potency assay development for advanced therapy medicinal products (ATMP). The team has also studied the stability of multi­potent stromal cell-based products and excipients that could play a key role extending the shelf-life of the critical quality attributes (CQA) of the nal product. Broad clinical experience has included cell-banking strategies for the production of clinical grade mesenchymal stromal cells from different tissues. Notable examples of potency assays from approved therapies are overviewed in Chap. 9.
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Moustapha Kassem a scientist, physician and endocrinologist based at the University Hospital of Odense, Denmark, has spearheaded the development of fully differentiating immortalised cell strains of human bone marrow­derived multipotent stromal cells (hBM-MSC), ideal for obtaining data con­cerning microarray gene expression analysis, microRNA regulation and proteomic phenotypes for identifying molecular signaling pathways directly associated with osteogenic differentiation. Chapter 4 describes extensive characterisation of the osteogenic biomarkers of human bone marrow-derived multipotent stromal cells (hBM-MSC) and their relevance for potency assays.
The unmet clinical need of cartilage regeneration for joint damage and osteoarthritis has also been an area of intense research. Consistent with a growing appreciation that cell-secreted factors can be of therapeutic benet, Lucienne A.Vonk’s research team at the University Medical Center Utrecht in the Netherlands demonstrated that extracellular vesicles derived from hBM-MSC can promote cartilage regeneration invitro. Chapter 5 provides insights into establishing potency assays that not only function with whole cells, but also acellular products derived from the cells.
Raghavan Chinnadurai at the Mercer University School of Medicine, USA, has explored multiparametric analysis of hBM-MSC for the purposes of characterising their potency to modulate the immune system. Secretome analysis has been compared with quantitative RNA-based gene array analysis targeting immunomodulatory and homing properties of MSC.In Chap. 6, he describes advanced technologies for potency assay measurement, discussing how diverse complementary approaches can enhance prospects for establish­ing specic potency biomarkers.
Developing Lab-on-chip devices for biomedical diagnostics, Despina Moschou at the University of Bath applies microfabrication and microelec­tronics with a view to meet the ASSURED criteria; Affordable, Sensitive, Specic, User friendly, Rapid analysis, Equipment-free and Delivered at point of care. As described with Sotirios Papamatthaiou in Chap. 7, adoption of a printed circuit board (PCB) platform would achieve these aims and be readily scalable for existing industrial platforms. Adapting the Lab-on-PCB approach to take advantage of alternative technologies would be particularly advantageous for high performance, efcient, cost-effective potency assays.
In Chap. 8, Claire Roddie, Associate Professor in Hematology at University College London (UCL) and consultant Hematologists at UCL Hospital, together with Juliana Dias and AmaiaCadiñanos-Garai, describes potency assays for one of the most signicant novel approaches to cell-mediated ther­apy, the use of chimeric antigen receptor T cells (CAR-T) that are genetically engineered to produce a tailored T-cell receptor for use in immunotherapy. Their pursuit of adoptive cell therapies involves pre-clinical development of novel CAR-T projects where the development of potency assays can be par­ticularly challenging given the complexity of the therapeutic modality.
Juli Mansnérus, Postdoctoral Researcher at the Faculty of Law, University of Helsinki, has published extensively on ATMP and ethical challenges of personalized medicine. Both Juli and co-author Waltter Roslin have partaken in the DECIDER project, exploring diagnostic tools and treatments for ovar­ian cancer using AI methods. This project has received funding from the
Preface
Preface
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European Union’s Horizon 2020 research and innovation programme under grant agreement No 965193 for DECIDER.Chapter 10 provides an impor­tant legal perspective on the integrity of potency assays as a basis safe clinical intervention, with appreciation of the manner, whereby ATMP regulations were set up as a lex specialis introducing particular provisions to the existing pharmaceutical legislation with respect to authorisation, supervision and pharmacovigilance of ATMP to ensure they are safe and effective.
It is signicant that ATMPs are usually developed by academia or within hospitals and involve small medium enterprise (SME) companies rather than big pharmaceutical companies that predominantly develop conventional medicines. However, the whole cell therapy sector, like potency assays, is in continuous evolution, and in the nal Chap. 11, an Editorial forward-looking perspective is presented, regarding many innovative technological develop­ments, institutional roles and guidance contributing to potency assay devel­opment in the future. A renewed focus on potency assays will help establish capabilities and standards for scientically sound reportable data to correlate product-specic biological activity with therapeutic activity and streamline the strategic development of advanced medicines with more cost-effective success.
Ferrara, Italy JorgeS.Burns
Contents
1 The Art of Stem Cell-Based Therapy . . . . . . . . . . . . . . . . . . . . . . 1
Jorge S. Burns
1.1 The Dawn of a New Era . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Lessons from a Past Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.3 Potency Assays for Modern Disease Intervention . . . . . . . . . . 4
1.4 From Viral Vaccination to Safe Therapy with Cells . . . . . . . . . 4
1.5 From Stem Cell Safety and Efcacy to Potency . . . . . . . . . . . 6
1.6 Complementing Stem Cell- Based Therapy Art
with Standard Operating Procedures . . . . . . . . . . . . . . . . . . . . 6
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2 Potency Assay Development: A Keystone for Clinical Use . . . . . 13
Raffaela Torggler, Eva Margreiter, Rainer Marksteiner, and Marco Thurner
2.1 Potency Assays as Part of Cell-Based ATMP Quality
Control Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.1.1 What Is a Potency Assay? . . . . . . . . . . . . . . . . . . . . . . 13
2.1.2 Regulatory Requirements for a Potency Assay . . . . . . 14
2.2 Approach to Develop a Potency Assay
for Cell- Based ATMPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.2.1 General Considerations . . . . . . . . . . . . . . . . . . . . . . . . 14
2.2.2 Progressive Implementation of a Potency Assay . . . . . 19
2.3 Clinical Value of Potency Assays . . . . . . . . . . . . . . . . . . . . . . . 20
2.3.1 Relationship Between Potency
and Clinical Efcacy . . . . . . . . . . . . . . . . . . . . . . . . . . 20
2.3.2 Potency and Dening an Effective Dose
for ATMPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
2.4 Potency Assay in Product and Process Development . . . . . . . 21
2.4.1 Stability Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.4.2 Comparability Studies . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.4.3 Compatibility Studies . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.5 State of the Art of Potency Assays for Cell-Based ATMPs . . . 23
2.5.1 Examples of Potency Assays
for Cell-Based ATMPs . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.5.2 Challenges to Potency Assay Development
for ATMPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
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