KRAS変異を標的とした二重特異性抗体を開発～膵がん・大腸がん患者の治療に応用期待～

2026-10-20

2026-10-19 医薬基盤・健康・栄養研究所

医薬基盤・健康・栄養研究所とがん研究会などの研究チームは、膵臓がんや大腸がんにみられるKRAS G12V変異由来のネオアンチゲンを標的とする二重特異性抗体を開発した。この抗体は、がん細胞表面のHLA分子に提示されたネオアンチゲンと、T細胞表面のCD3分子の両方に結合することで、T細胞をがん細胞に誘導し、攻撃させる仕組みを持つ。従来、ネオアンチゲンを標的とする治療では、患者ごとに異なるHLA型が治療薬の適用範囲を制限する課題があった。今回開発した抗体は、HLA-A11:01に提示されたネオアンチゲンだけでなく、HLA-A03:01に提示されたものも認識できることが示された。マウスの移植腫瘍モデルでは、腫瘍の増大を抑制した。KRAS G12V変異とHLA型の頻度に基づく推計では、膵臓がん患者の約5％、大腸がん患者の約2％が治療対象となる可能性がある。本成果は、複数のHLA型に対応するがん免疫療法の開発につながるものであり、今後の臨床応用に向けた研究が期待される。

＜関連情報＞

HLA-A11:01とHLA-A03:01の両方にまたがるKRAS G12Vネオアンチゲンを標的とするT細胞活性化二重特異性抗体の設計 Engineering T cell-engaging bispecific antibodies targeting KRAS G12V neoantigen across HLA-A11:01 and HLA-A03:01

Xiaojing Wu,Clara Effenberger,Yosuke Matsushita,Hiroki Tanaka,Yu Ishii,Suyong Re,…
Journal for ImmunoTherapy of Cancer Published:18 October 2026
DOI:10.1136/jitc-2026-016411

Abstract

Background T cells recognize tumor-specific neoantigens presented by human leukocyte antigen (HLA) molecules and can mediate potent antitumor immunity. However, most neoantigens are patient-specific, limiting their broad therapeutic applicability. KRAS G12V is a recurrent oncogenic mutation found in multiple cancer types and generates a shared neoantigen presented by HLA-A*11:01. We sought to develop a T cell-engaging bispecific antibody targeting this shared neoantigen.

Methods We screened a phage display library to identify a single-chain variable fragment (scFv) recognizing the KRAS G12V/HLA-A*11:01 complex. Candidate scFvs were characterized by ELISA and flow cytometry. A bispecific single-chain diabody incorporating a neoantigen-specific scFv and an anti-CD3 binding domain was generated and evaluated for antigen-specific T-cell activation, cytokine production, and cytotoxicity using peptide-pulsed target cells and KRAS G12V-positive cancer cell lines. Antitumor activity and safety were assessed in a human peripheral blood mononuclear cell (PBMC)-engrafted xenograft mouse model.

Results We identified scFv2, which selectively recognized the KRAS G12V/HLA-A*11:01 complex while discriminating against wild-type KRAS and other KRAS mutant peptides. Notably, scFv2 also recognized the KRAS G12V/HLA-A*03:01 complex. The resulting scFv2-based bispecific single-chain diabody (scDb2) induced robust antigen-specific T-cell activation, cytokine release and cytotoxicity against KRAS G12V-positive cancer cells expressing either HLA-A*11:01 or HLA-A*03:01, corresponding to an estimated patient coverage of ~5–6% in pancreatic cancer and ~2% in colorectal cancer. scDb2 recognized an endogenously processed and presented neoantigen, mediated cancer cell killing, and significantly suppressed tumor growth in vivo without overt toxicity.

Conclusion These findings identify a T cell-engaging bispecific antibody capable of recognizing KRAS G12V presented by both HLA-A*11:01 and HLA-A*03:01, providing a framework for expanding neoantigen-targeted immunotherapies across closely related HLA alleles, potentially broadening applicability across diverse patient populations.