2025-09-25 カリフォルニア大学アーバイン校(UCI)
<関連情報>
- https://news.uci.edu/2025/09/25/unique-pan-cancer-immunotherapy-destroys-tumors-without-attacking-healthy-tissue-uc-irvine-study-shows/
- https://www.cell.com/cell/fulltext/S0092-8674(25)01032-3
腫瘍関連糖鎖抗原をベルクロのような密度依存的に標的とする、安全な免疫抑制抵抗性全癌免疫療法 Safe immunosuppression-resistant pan-cancer immunotherapeutics by velcro-like density-dependent targeting of tumor-associated carbohydrate antigens
Raymond W. Zhou ∙ Paresh Kumar Purohit ∙ Jai Hyun Kim ∙ … ∙ Barbara L. Newton ∙ Robert A. Edwards ∙ Michael Demetriou
Cell Published:September 25, 2025
DOI:https://doi.org/10.1016/j.cell.2025.09.001
Graphical abstract
Highlights
- “Velcro-like” lectin targeting of high-density carbohydrate antigens in diverse cancers
- High-avidity binding directs T cells to cancer but not low-density normal cells
- Checkpoint inhibition of β1,6-branching overcomes immunosuppressive tumor environments
- High-potency pan-cancer immunotherapy without “on-target, off-cancer” toxicity
Summary
Bispecific antibodies and chimeric antigen receptor T cells are some of the most potent cancer immunotherapeutics in clinical use, yet most cancers remain poorly targetable. High-affinity antibodies required to maximize killing detect low antigen expression in normal tissue, risking “on-target, off-cancer” toxicity. This compels identification of cancer-restricted cell-surface protein antigens, which are rare. Tumor-associated carbohydrate antigens (TACAs) are the most abundant and widespread cancer antigens known but are poorly targetable by antibodies. Here, we describe glycan-dependent T cell recruiter (GlyTR) pan-cancer immunotherapeutics that utilize high-avidity “velcro-like” lectin binding to kill cells with high but not low TACA expression. GlyTR1 and GlyTR2 bind immunosuppressive β1,6GlcNAc-branched N-glycans or multiple TACAs (Tn, sialyl-Tn, LacDiNAc, and GD2), respectively, overcome immunosuppressive mechanisms in the tumor microenvironment and trigger target-density-dependent T cell-mediated pan-cancer killing, yet they lack toxicity in mice with human-like TACA expression. Density-dependent lectin binding to TACAs provides highly potent and safe pan-cancer immunotherapeutics.
