RHEACELL GmbH & Co. KG, Heidelberg, Germany.
TICEBA GmbH, Heidelberg, Germany.
Cytotherapy. 2019 May;21(5):546-560. doi: 10.1016/j.jcyt.2018.12.005. Epub 2019 Mar 14.
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 × 10 ABCB5 MSCs/animal and intravenous application of 2 × 10 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 × 10 to 1 × 10 cells/animal and three biweekly intravenous injections of 2 × 10 ABCB5 MSCs/animal, respectively, to immunocompromised mice were nontoxic and revealed no tumorigenic potential; and (iii) intramuscular injection of 5 × 10 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.
人类皮肤 ABCB5 表达间充质基质细胞（ABCB5 MSC）是目前几种再生医学领域中多种目前无法治愈疾病的干细胞治疗的有前途的候选物。我们已经开发并验证了一种从人类皮肤样本中分离和扩增符合国际细胞治疗学会指南标准的 ABCB5 MSC 的方法。我们能够将这些细胞加工成符合良好生产规范的、基于 MSC 的高级治疗药物产品。
为了支持 ABCB5 MSC 用于潜在的治疗性局部、肌肉内和静脉内给药，我们已经在一系列符合良好实验室规范的非临床体内研究中测试了我们的产品，这些研究涵盖了生物安全性的所有相关方面，包括潜在的长期持久性和增殖、向非靶组织的分布、向不需要的细胞类型分化、异位组织形成、肿瘤形成和局部组织反应。
（i）分别向免疫功能低下的小鼠皮下应用 1×10 ABCB5 MSC/只和静脉内应用 2×10 ABCB5 MSC/只，不会导致细胞的安全性相关分布、持久性或增殖；（ii）分别向免疫功能低下的小鼠皮下注射 1×10 至 1×10 细胞/只范围内的 3 次每月剂量的 ABCB5 MSC 和 3 次双周静脉内注射 2×10 ABCB5 MSC/只，均无毒性且没有肿瘤形成潜力；（iii）向免疫功能低下的小鼠肌肉内注射 5×10 ABCB5 MSC 局部耐受性良好。
本临床前体内数据证明了基于人皮肤源性 ABCB5 MSC 的新型高级治疗药物产品的局部和全身安全性和耐受性。
