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Production and nonclinical evaluation of an autologous iPSC-derived platelet product for the iPLAT1 clinical trial

Sugimoto, Naoshi Nakamura, Sou Shimizu, Shin Shigemasa, Akiko Kanda, Junya Matsuyama, Nobuki Tanaka, Mitsunobu Hayashi, Tomoya Fuchizaki, Akihiro Nogawa, Masayuki Watanabe, Naohide Okamoto, Shinichiro Handa, Makoto Sawaguchi, Akira Momose, Dai Koh, Ki-Ryang Tani, Yoshihiko Takaori-Kondo, Akifumi Eto, Koji 京都大学 DOI:10.1182/bloodadvances.2022008512

2022.12.13

概要

Donor-derived platelets are used to treat or prevent hemorrhage in patients with thrombocytopenia. However, ∼5% or more of these patients are complicated with alloimmune platelet transfusion refractoriness (allo-PTR) due to alloantibodies against HLA-I or human platelet antigens (HPA). In these cases, platelets from compatible donors are necessary, but it is difficult to find such donors for patients with rare HLA-I or HPA. To produce platelet products for patients with aplastic anemia with allo-PTR due to rare HPA-1 mismatch in Japan, we developed an ex vivo good manufacturing process (GMP)–based production system for an induced pluripotent stem cell–derived platelet product (iPSC-PLTs). Immortalized megakaryocyte progenitor cell lines (imMKCLs) were established from patient iPSCs, and a competent imMKCL clone was selected for the master cell bank (MCB) and confirmed for safety, including negativity of pathogens. From this MCB, iPSC-PLTs were produced using turbulent flow bioreactors and new drugs. In extensive nonclinical studies, iPSC-PLTs were confirmed for quality, safety, and efficacy, including hemostasis in a rabbit model. This report presents a complete system for the GMP-based production of iPSC-PLTs and the required nonclinical studies and thus supports the iPLAT1 study, the first-in-human clinical trial of iPSC-PLTs in a patient with allo-PTR and no compatible donor using the autologous product. It also serves as a comprehensive reference for the development of widely applicable allogeneic iPSC-PLTs and other cell products that use iPSC-derived progenitor cells as MCB.

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