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

Abstract

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. 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. (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. 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.