Full GMP-compliant validation of bone marrow-derived human CD133(+) cells as advanced therapy medicinal product for refractory ischemic cardiomyopathy.

Daniela Belotti,Giuseppe Gaipa,Laura Cavallotti,Gabriella Spaltro,Giulio Pompilio,Matteo Parma,Elisa Gambini,Beatrice Bassetti,Andrea Biondi,Benedetta Cabiati,Ettore Biagi

doi:10.1155/2015/473159

Abstract

According to the European Medicine Agency (EMA) regulatory frameworks, Advanced Therapy Medicinal Products (ATMP) represent a new category of drugs in which the active ingredient consists of cells, genes, or tissues. ATMP-CD133 has been widely investigated in controlled clinical trials for cardiovascular diseases, making CD133+ cells one of the most well characterized cell-derived drugs in this field. To ensure high quality and safety standards for clinical use, the manufacturing process must be accomplished in certified facilities following standard operative procedures (SOPs). In the present work, we report the fully compliant GMP-grade production of ATMP-CD133 which aims to address the treatment of chronic refractory ischemic heart failure. Starting from bone marrow (BM), ATMP-CD133 manufacturing output yielded a median of 6.66 × 106 of CD133+ cells (range 2.85 × 106–30.84 × 106), with a viability ranged between 96,03% and 99,97% (median 99,87%) and a median purity of CD133+ cells of 90,60% (range 81,40%–96,20%). Based on these results we defined our final release criteria for ATMP-CD133: purity ≥ 70%, viability ≥ 80%, cellularity between 1 and 12 × 106 cells, sterile, and endotoxin-free. The abovementioned criteria are currently applied in our Phase I clinical trial (RECARDIO Trial).

Highlights

In the last decade, bone marrow (BM) and peripheral blood(PB-) derived CD133+ endothelial progenitor cells have been tested in controlled clinical trials as therapeutic agent for heart failure both in acute [1, 2] and chronic [3, 4] setting, with the aim to achieve neoangiogenesis in ischemic myocardial territories
According to the European Medicine Agency (EMA) regulatory frameworks, Advanced Therapy Medicinal Products (ATMP) represent a new category of drugs in which the active ingredient consists of cells, genes, or tissues
BioMed Research International differentiating into newly forming vessels [17] and, predominantly, by indirectly activating proangiogenic signaling through indirect paracrine mechanisms [7, 18]. Due to their nonhomologous use, notwithstanding immunomagnetically clinical-grade purified [19], CD133+ progenitors [20] have to be considered in the cardiovascular setting as an Advanced Therapy Medicinal Products (ATMP), in compliance with the European Medicine Agency (EMA) guidelines [21] and the Committee of Advance Therapies (CAT) Reflection paper on human stem cell-based medicinal product [22]

Summary

Introduction

Bone marrow (BM) and peripheral blood(PB-) derived CD133+ endothelial progenitor cells have been tested in controlled clinical trials as therapeutic agent for heart failure both in acute [1, 2] and chronic [3, 4] setting, with the aim to achieve neoangiogenesis in ischemic myocardial territories. BioMed Research International differentiating into newly forming vessels [17] and, predominantly, by indirectly activating proangiogenic signaling through indirect paracrine mechanisms [7, 18] Due to their nonhomologous use, notwithstanding immunomagnetically clinical-grade purified [19], CD133+ progenitors [20] have to be considered in the cardiovascular setting as an Advanced Therapy Medicinal Products (ATMP), in compliance with the European Medicine Agency (EMA) guidelines [21] and the Committee of Advance Therapies (CAT) Reflection paper on human stem cell-based medicinal product [22]. The final CD133+ cell product must be released upon a strict manufacturing characterization, as well as definition of release criteria and quality controls This validation process is the prerequisite for the release of batches intended for clinical use

Methods

Results

Conclusion