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Advances in Experimental Medicine and Biology 1420
JorgeS.BurnsEditor
Potency Assays
forAdvanced
Stem Cell Therapy
Medicinal Products

Advances in Experimental Medicine
and Biology
Volume 1420
Series Editor
WimE.Crusio, Institut de Neurosciences Cognitives et Intégratives
d’Aquitaine, CNRS and University of Bordeaux, Pessac Cedex,France
HaidongDong, Departments of Urology and Immunology,Mayo Clinic,
Rochester,MN,USA
HeinfriedH.Radeke, Institute of Pharmacology and Toxicology,
Clinic of the Goethe University Frankfurt Main,
Frankfurt am Main,Hessen,Germany
NimaRezaei, Research Center for Immunodeciencies,
Children’s Medical Center,Tehran University of Medical Sciences,
Tehran,Iran
OrtrudSteinlein, Institute of Human Genetics,
LMU University Hospital,Munich,Germany
JunjieXiao, 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
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biomedical engineering, genetics, physiology, and cancer research. Covering
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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
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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 reections 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 fromthe 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 pragmaticprogress
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.
vii

viii
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 benet,
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 invitro. 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 specic 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,
Specic, 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, efcient, 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 AmaiaCadiñanos-Garai, describes potency
assays for one of the most signicant 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
ix
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 signicant 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 scientically sound reportable data to correlate
product-specic biological activity with therapeutic activity and streamline
the strategic development of advanced medicines with more cost-effective
success.
Ferrara, Italy JorgeS.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 Efcacy 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 Efcacy . . . . . . . . . . . . . . . . . . . . . . . . . . 20
2.3.2 Potency and Dening 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
xi
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