Neutralizing antibody producing B cell deletion by CAR technology in Lysosomal diseases

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K22540
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Gojo Satoshi 京都府立医科大学, 医学(系)研究科(研究院), 教授 (90316745)
• Co-Investigator(Kenkyū-buntansha): 星野 温 京都府立医科大学, 医学(系)研究科(研究院), 助教 (50737210) ; 上 大介 京都府立医科大学, 医学(系)研究科(研究院), 講師 (80415588)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Keywords: CAR T / 中和抗体 / ライソゾーム病 / Electroporation / mRNA

Outline of Final Research Achievements

Lysosomal diseases are inherited metabolic disorders caused by the deficiency enzymes in lysosomes, organelles within cells. Fabry disease is one of these lysosomal diseases, and alpha-galactosidase (GLA) is the causative gene. The current treatment of Fabry disease is ERT using GLA protein. However, almost male patients produce neutralizing antibodies to recombinant GLA proteins in their bodies, reducing the efficacy of ERT. We attempted to develop a novel therapeutic approach (BAR) to specifically eliminate B cells that produce GLA neutralizing antibodies. We constructed an evaluation system using cell lines to evaluate the efficacy of BAR, and evaluated the efficacy of several design sequences. We also designed a model cell line for GLA antibody-producing B cells and constructed a system for the expression of scFv to GLA on the cell surface. By using the above systems, we designed and constructed a system that enables us to search for effective sequences and the efficacy of BAR.

Free Research Field

病理病態学、感染・免疫学およびその関連分野

Academic Significance and Societal Importance of the Research Achievements

CAR-Tが臨床の場において大きなインパクトを与えている。この技術は自己免疫疾患への応用も期待されているが、具体的な展開は殆どなされてない。特に中和抗体の抑制を目的とした利用はなされておらず、ファブリー病の酵素製剤に対する中和抗体産生B細胞消去の検討は新規性の高い研究である。この研究成果は中和抗体が関与する病態に適応できるため、他のライソゾーム病や血友病への展開も期待されるため、その意義は大きい。またアナフィラキシーへの効果的な介入に展開できる可能性もあるため、本アプローチは極めてユニークでオリジナリティが高いProof of Conceptを証明する萌芽的な研究である。