In vivo safety profile and biodistribution of GMP-manufactured human skin-derived ABCB5-positive mesenchymal stromal cells for use in clinical trials.

Abstract

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.

• Authors: Nils Tappenbeck, Hannes M Schröder, Elke Niebergall-Roth, Fathema Hassinger, Ulf Dehio, Kathrin Dieter, Korinna Kraft, Andreas Kerstan, Jasmina Esterlechner, Natasha Y Frank, Karin Scharffetter-Kochanek, George F Murphy, Dennis P Orgill, Joachim Beck, Markus H Frank, Christoph Ganss, Mark A Kluth
• Journal: Cytotherapy (Cytotherapy) Vol. 21 Issue 5 Pg. 546-560 (05 2019) ISSN: 1477-2566 [Electronic] England
• PMID: 30878384 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 International Society for Cell and Gene Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• ABCB5 protein, human
• ATP Binding Cassette Transporter, Subfamily B

Topics

• ATP Binding Cassette Transporter, Subfamily B (metabolism)
• Administration, Intravenous
• Animals
• Cell Differentiation
• Female
• Humans
• Injections, Intramuscular
• Male
• Mesenchymal Stem Cell Transplantation (adverse effects, methods, standards)
• Mesenchymal Stem Cells (cytology, metabolism)
• Mice, Inbred NOD
• Quality Control
• Skin (cytology)
• Tissue Distribution