Novel Immunotherapies Targeting Cisplatin Resistance Molecular Mechanisms.

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K20777
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0803:Pathology, infection/immunology, and related fields
• Research Institution: Sapporo Medical University
• Principal Investigator: MIZUE Yuka 札幌医科大学, 医学部, 研究員 (20464480)
• Project Period (FY): 2022-08-31 – 2024-03-31
• Keywords: 抗体工学 / シスプラチン耐性 / 癌抗原 / 抗体医薬

Outline of Final Research Achievements

We developed a recombinant single-chain variable fragment (scFv) antibody targeting the HLA-A2/Claspin peptide complex, whose presentation is enhanced in cisplatin-resistant cells. Next, using this scFv, we designed a bispecific T-cell engager antibody (BiTE Ab) that recognizes both the HLA-A2/Claspin peptide complex and CD3 molecules. Additionally, aiming for optimal formulation in terms of therapeutic efficacy and safety, we constructed a bivalent antibody (scFv-hIgG1 Fc) where the human IgG1 Fc region was fused to the scFv, and chimeric antigen receptor (CAR) T cells where the CD3ζ activation domain and CD28 transmembrane domain were fused. We evaluated their functionalities and confirmed their interaction with HLA-A2/Claspin peptide-expressing cells. Furthermore, we confirmed that the BiTE antibody could induce strong cytotoxic activity against its target cells, cisplatin-resistant bladder cancer, using WST-8 and LDH activity measurements.

Free Research Field

がん免疫

Academic Significance and Societal Importance of the Research Achievements

これまで承認された抗体医薬は、いずれも治療標的となるがん全般に発現する分子を標的としていた。しかし、遺伝学的、機能的に多様ながんの根治を目指す上で、機能的多様性に対応できる治療薬およびバイオマーカーの開発が重要になる。我々は、シスプラチン耐性がん細胞に発現する治療標的として HLA-A2が提示するClaspinペプチドを同定し、本研究において、これを標的しうる特異的抗体を開発した。Claspin は膀胱癌のみならず、腎癌、前立腺癌など様々な癌種においても高発現し、プラチナ製剤耐性を示す悪性腫瘍全般が標的となる可能性がある。シスプラチン耐性癌に対する新規治療薬開発の一助となることが期待される。