Mechanisms governing intracellular accumulation of mutant CALR proteins

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K16127
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Juntendo University
• Principal Investigator: Yoshihiko Kihara 順天堂大学, 医学部, 博士研究員 (70812999)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 造血器腫瘍 / 骨髄増殖性腫瘍 / calreticulin / 細胞内蓄積 / 蛋白質分解経路 / 蛋白質分泌経路 / 蛋白質の切断 / 抗体医療

Outline of Final Research Achievements

In this study, we aimed to elucidate the regulatory mechanism of intracellular accumulation of mutant CALR proteins that causes myeloproliferative neoplasms (MPNs). As a result, it was found that the majority of mutant CALR proteins exist as low molecular weight forms that could not be detected by existing antibodies. Antibodies against the low-molecular-weight mutant CALR protein that was thought to be cleaved by a protease(s) were generated. The antibodies bound strongly to both the full-length and low-molecular-weight mutant CALR proteins. Chimeric antibodies and bispecific antibodies based on the antibodies exhibited their potential as therapeutic agents for MPN patients with CALR mutations.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

本研究により、世界に先駆けて、骨髄増殖性腫瘍（MPN）の発症原因分子である変異型CALR蛋白質の細胞内蓄積制御メカニズムが明らかになった。さらに、既存の抗体では検出されない低分子量の変異型CALR蛋白質の捕捉を可能とする抗体も開発できた。そして、この抗体がCALR遺伝子変異を有するMPN患者に対する治療薬として有望であることが示された。これらの研究成果は、CALR遺伝子変異によるMPN発症メカニズムを明らかにしただけでなく、変異型CALR蛋白質を標的とする新規治療戦略の開発の道筋を提示しており、学術的にも社会的にも意義深いと言える。