Innovations in anti-CCR4 antibody therapy based on elucidation of molecular dynamics of CCR4 mutants

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15567
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Nagoya University
• Principal Investigator: Hiramatsu Hiroaki 名古屋大学, 医学系研究科, 研究員 (70827253)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: ATLL / CCR4 / モガムリズマブ

Outline of Final Research Achievements

In this study, I analyzed genetic mutations in ATLL patients before and after treatment with mogamulizumab. C-terminal deletion mutant of CCR4, which is observed in around 30% of ATLL patients, was found to induce ligand-dependent anti-apoptotic signals, and several proteins were identified that may bind to CCR4 of C-terminal deletion mutant specifically. Analysis using pre- and post-treatment PBMCs from ATLL patients who acquired resistance during Mogamulizumab treatment revealed that CCR4 mutations associated with resistance occurred only after treatment. Among them, CCR4 with mutations in transmembrane regions could be localized to the cell surface by adding a small molecule compound that binds to CCR4, restoring the cytotoxic activity of Mogamulizumab, indicating its potential as a future combinatorial drug.

Free Research Field

腫瘍免疫学

Academic Significance and Societal Importance of the Research Achievements

本研究により、CCR4のC末端欠損変異は、正常T細胞に対しても生存に対する優位性を付与することのできる細胞内シグナルを生じさせている可能性が示された。この結果は、ATLLの発症にかかわるシグナルの一端の解明に寄与するものである。また、モガムリズマブ耐性にかかわるCCR4遺伝子変異の耐性化の機序と、それを克服できる可能性のある小分子化合物を発見した。この成果は、将来のモガムリズマブとの併用薬の開発につながることが期待され、ATLL治療法の改善に資する成果である。