Method for improving car-t cell effector functions by targeted degradation of glycosylated PD-1
By using a P-TrCP-TP ubiquitin ligase to target and degrade PD-1 on CAR-T cells, the therapy enhances CAR-T cell efficacy against solid tumors, addressing the limitations of existing protein degradation strategies and immune checkpoint suppression.
WO2026136906A2PCT designated stage Publication Date: 2026-06-25CORNELL UNIVERSITY
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- CORNELL UNIVERSITY
- Filing Date
- 2025-12-19
- Publication Date
- 2026-06-25
AI Technical Summary
Technical Problem
Current CAR-T cell therapy is less effective against solid tumors due to the suppressive tumor microenvironment, where PD-1/PD-L1 signaling inhibits T-cell functions, and existing protein degradation strategies like PROTACs have limitations in targeting all proteins.
Method used
A chimeric complex of P-TrCP-TP SCF E3 ubiquitin ligase is genetically linked to a targeting peptide to selectively degrade glycosylated PD-1 on CAR-T cells, enhancing their effector functions and anti-tumor activity.
Benefits of technology
The targeted degradation of PD-1 improves CAR-T cell efficacy and durability against solid tumors by overcoming immune checkpoint inhibition, promoting ex vivo expansion and in vivo proliferation.
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Smart Images
Figure US2025060696_25062026_PF_FP_ABST
Abstract
The present invention genetically links a small targeting peptide (TP) to E3 ubiquitin ligase β-TrCP and deplete glycosylated, degradation-resistant PD-1 protein from cells by protein knockout technology. The chimeric β-TrCP-TP ubiquitin ligase specifically directs to both glycosylated and non-glycosylated PD-1 protein for destruction. Targeted degradation of endogenous PD-1 by the present invention also promotes marked expansion of CAR T-cells, which is useful in cancer immunotherapy. In one embodiment, TP is a peptide that binds to PD-1, for example, it is SH2 (C) and / or SH2 (N) domains of Tyrosine phosphatase SHP2. The present application demonstrates that N-linked glycosylation prevents PD-1 from undergoing GSK3β / β-TrCP-mediated ubiquitination and subsequent degradation. Using a "protein knockout" (PKO)-based targeted protein degradation strategy, the present method selectively depletes glycosylated PD-1, thereby enhances the ex vivo expansion of CAR T cells. This PKO strategy can be directly incorporated into the CAR T vector, facilitating concurrent delivery of both CAR and PKO, and obviating the need for separate therapeutic regimens of CAR T and anti-PD-1 therapies. The integration of CAR and PKO into a single CAR T vector may significantly enhance the efficacy and durability of CAR T-based immunotherapies.
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