Abstract
BackgroundHuman dermal mesenchymal stromal cells (MSCs) expressing the ATP-binding cassette (ABC) efflux transporter ABCB5 represent an easily accessible MSC population that, based on preclinical and first-in-human data, holds significant promise to treat a broad spectrum of conditions associated not only with skin-related but also systemic inflammatory and/or degenerative processes.MethodsWe have developed a validated Good Manufacturing Practice-compliant expansion and manufacturing process by which ABCB5+ MSCs derived from surgical discard skin tissues are processed to an advanced-therapy medicinal product (ATMP) for clinical use. Enrichment for ABCB5+ MSCs is achieved in a three-step process involving plastic adherence selection, expansion in a highly efficient MSC-selecting medium, and immunomagnetic isolation of the ABCB5+ cells from the mixed culture.ResultsProduct Quality Review data covering 324 cell expansions, 728 ABCB5+ MSC isolations, 66 ABCB5+ MSC batches, and 85 final drug products reveal high process robustness and reproducible, reliable quality of the manufactured cell therapy product.ConclusionWe have successfully established an expansion and manufacturing process that enables the generation of homogenous ABCB5+ MSC populations of proven biological activity manufactured as a standardized, donor-independent, highly pure, and highly functional off-the-shelf available ATMP, which is currently tested in multiple clinical trials.
Highlights
Human dermal mesenchymal stromal cells (MSCs) expressing the ATP-binding cassette (ABC) efflux transporter ABCB5 represent an accessible Mesenchymal stromal cell (MSC) population that, based on preclinical and first-in-human data, holds significant promise to treat a broad spectrum of conditions associated with skin-related and systemic inflammatory and/or degenerative processes
Covering all three principal mechanisms by which MSCs can contribute to inflammation control and tissue repair, skin-derived ABCB5+ MSCs offer a broad spectrum of potential therapeutic indications associated with skinrelated and systemic inflammatory and/or degenerative processes
Aiming at developing human skin-derived ABCB5+ MSCs for clinical use as an advanced-therapy medicinal product (ATMP), we have developed and validated a Good Manufacturing Practice (GMP)-compliant ex vivo expansion and manufacturing process to reliably, reproducibly, and efficiently generate highly pure ABCB5+ MSCs of proven biological potency that can be instantly manufactured as an off-the-shelf product at a clinical scale
Summary
Human dermal mesenchymal stromal cells (MSCs) expressing the ATP-binding cassette (ABC) efflux transporter ABCB5 represent an accessible MSC population that, based on preclinical and first-in-human data, holds significant promise to treat a broad spectrum of conditions associated with skin-related and systemic inflammatory and/or degenerative processes. Human skin-derived ABCB5+ cells display typical MSC characteristics as defined by the International Society for Cellular Therapy [5], including adherence to plastic surfaces; clonogenicity; expression of CD90, CD73, and CD105; lack of hematopoietic lineage markers CD45, CD34, and CD14; increased osteogenic, adipogenic, and chondrogenic differentiation potential as compared with donor-matched ABCB5− fibroblasts [6]; and trans-differentiation into CD31+ endothelial cells [7]. In a first in-human clinical trial, topically applied ex vivo-expanded ABCB5+ MSCs facilitated wound closure of standard therapyresistant chronic venous ulcers [7]
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