TY  - JOUR
A1  - Tappenbeck, Nils
A1  - Schröder, Hannes M.
A1  - Niebergall-Roth, Elke
A1  - Hassinger, Fathema
A1  - Dehio, Ulf
A1  - Dieter, Kathrin
A1  - Kraft, Korinna
A1  - Kerstan, Andreas
A1  - Esterlechner, Jasmina
A1  - Frank, Natasha Y.
A1  - Scharffetter-Kochanek, Karin
A1  - Murphy, George F.
A1  - Orgill, Dennis P.
A1  - Beck, Joachim
A1  - Frank, Markus H.
A1  - Ganss, Christoph
A1  - Kluth, Mark A.
T1  - In vivo safety profile and biodistribution of GMP-manufactured human skin-derived ABCB5-positive mesenchymal stromal cells for use in clinical trials
JF  - Cytotherapy
N2  - Background aims
Human dermal ABCB5-expressing mesenchymal stromal cells (ABCB5+ MSCs) represent a promising candidate for stem cell–based therapy of various currently uncurable diseases in several fields of regenerative medicine. We have developed and validated a method to isolate, from human skin samples, and expand ABCB5+ MSCs that meet the guideline criteria of the International Society for Cellular Therapy. We are able to process these cells into a Good Manufacturing Practice–conforming, MSC-based advanced-therapy medicinal product.

Methods
To support the development of ABCB5+ MSCs for potential therapeutic topical, intramuscular and intravenous administration, we have tested our product in a series of Good Laboratory Practice–compliant nonclinical in-vivo studies addressing all relevant aspects of biosafety, including potential long-term persistence and proliferation, distribution to nontarget tissues, differentiation into undesired cell types, ectopic tissue formation, tumor formation and local tissue reaction.

Results
(i) Subcutaneous application of 1 × 107 ABCB5+ MSCs/animal and intravenous application of 2 × 106 ABCB5+ MSCs/animal, respectively, to immunocompromised mice did not result in safety-relevant biodistribution, persistence or proliferation of the cells; (ii) three monthly subcutaneous injections of ABCB5+ MSCs at doses ranging from 1 × 105 to 1 × 107 cells/animal and three biweekly intravenous injections of 2 × 106 ABCB5+ MSCs/animal, respectively, to immunocompromised mice were nontoxic and revealed no tumorigenic potential; and (iii) intramuscular injection of 5 × 106 ABCB5+ MSCs/animal to immunocompromised mice was locally well tolerated.

Discussion
The present preclinical in vivo data demonstrate the local and systemic safety and tolerability of a novel advanced-therapy medicinal product based on human skin-derived ABCB5+ MSCs.
KW  - stromal cells
KW  - stem cells
KW  - MSC
KW  - biodistribution
KW  - safety
KW  - ABCB5
KW  - GMP
KW  - tumorigenicity
KW  - toxicity
KW  - persistence
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240456
VL  - 21
ER  - 
TY  - JOUR
A1  - Haeusner, Sebastian
A1  - Herbst, Laura
A1  - Bittorf, Patrick
A1  - Schwarz, Thomas
A1  - Henze, Chris
A1  - Mauermann, Marc
A1  - Ochs, Jelena
A1  - Schmitt, Robert
A1  - Blache, Ulrich
A1  - Wixmerten, Anke
A1  - Miot, Sylvie
A1  - Martin, Ivan
A1  - Pullig, Oliver
T1  - From Single Batch to Mass Production–Automated Platform Design Concept for a Phase II Clinical Trial Tissue Engineered Cartilage Product
JF  - Frontiers in Medicine
N2  - Advanced Therapy Medicinal Products (ATMP) provide promising treatment options particularly for unmet clinical needs, such as progressive and chronic diseases where currently no satisfying treatment exists. Especially from the ATMP subclass of Tissue Engineered Products (TEPs), only a few have yet been translated from an academic setting to clinic and beyond. A reason for low numbers of TEPs in current clinical trials and one main key hurdle for TEPs is the cost and labor-intensive manufacturing process. Manual production steps require experienced personnel, are challenging to standardize and to scale up. Automated manufacturing has the potential to overcome these challenges, toward an increasing cost-effectiveness. One major obstacle for automation is the control and risk prevention of cross contaminations, especially when handling parallel production lines of different patient material. These critical steps necessitate validated effective and efficient cleaning procedures in an automated system. In this perspective, possible technologies, concepts and solutions to existing ATMP manufacturing hurdles are discussed on the example of a late clinical phase II trial TEP. In compliance to Good Manufacturing Practice (GMP) guidelines, we propose a dual arm robot based isolator approach. Our novel concept enables complete process automation for adherent cell culture, and the translation of all manual process steps with standard laboratory equipment. Moreover, we discuss novel solutions for automated cleaning, without the need for human intervention. Consequently, our automation concept offers the unique chance to scale up production while becoming more cost-effective, which will ultimately increase TEP availability to a broader number of patients.
KW  - ATMP
KW  - tissue engineering
KW  - GMP
KW  - manufacturing
KW  - autologous
KW  - cartilage regeneration
KW  - automation & robotics
KW  - automation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244631
SN  - 2296-858X
VL  - 8
ER  -