Q6*
iTAG (“Inducible and TArgeted protein DeGradation”) Platform: Drug‑Inducible Degron Tags for Adoptive Cell‑Based Immunotherapies
Prof. Ian Collins, ICR; Prof. Louis Chesler, ICR; Prof. John Anderson, UCL; Dr Yann-Vai Le Bihan , ICR
Cancer Research Horizons
Challenge
In solid tumour and relapsed leukaemia/lymphoma patients, Chimeric Antigen Receptor (CAR) T-cell success is constrained by multifactorial mechanisms; however, evidence suggests dominant shared barriers are inadequate engraftment and T cell exhaustion.
The iTAG drug-inducible degron platform is designed to address these bottlenecks by enabling pharmacologically controlled, reversible downregulation of CAR surface expression through targeted degradation in the presence of synergistic Immunomodulatory drugs (IMiDs)/CELMoDs (Cereblon E3 ligase modulators). This tunable OFF-switch provides temporal control of CAR, with the aim of mitigating T-cell exhaustion while ultimately preserving CAR-T functionality and persistence post-infusion.
Technology
iMIDs act as molecular glues, promoting CRL4CRBN E3 ligase-neosubstrate complex formation, inducing ubiquitination and proteasomal degradation. Institute of Cancer Research (ICR) researchers developed “iTAG”, which centres on the novel design of drug-inducible tags composed of zinc finger protein degron containing domains (DCD) that selectively interact with CRL4CRBN in the presence of IMiDs/CELMoDs.
iTAG was shown to induce the rapid (down to 15 min) and efficient (>80%) degradation of various fusion protein targets across multiple cell types in-vitro using several IMiDs/CELMoDs small molecules such as thalidomide, lenalidomide, pomalidomide, CC-122 and CC-220. Additionally, in-vivo a single oral dose of CC-220 can induce the loss of iTAG-fused proteins as early as ~4 hours post administration.
ICR and University College London (UCL) researchers developed the “iTAG2” platform, which fuses an improved DCD sequence “iTAG2”, with chimeric antigen receptors to control CAR-T cells. Importantly, iTAG2 preserved CAR cell surface expression and strong CAR-T cell functionality. iTAG outperforms other approaches, overcoming limitations of SuperDegron, dTAGs, state-of-the-art PROTACs, by avoiding issues such as hook-effect whilst ensuring suitable dosing and efficient protein modulation.
Commercial Opportunity
The iTAG platform seeks to unlock the untapped potential of CAR-T in cancers, particularly solid tumours. iTAGs can seamlessly integrate with CARs, requiring no binder redesign. During manufacturing, iTAG could be exploited to suppress toxic signalling and optimise CAR-T cell fitness pre-infusion. Trials will initiate Q3 2026, positioning iTAG as the first IMiD-induced degron tag CAR platform to be validated in cancer patients. We now seek licensing/co-development partners to integrate iTAG into next-generation oncology CAR-T products.
Development Status
Large translational grants (totalling >£5m), from MRC DPFS CRH/CRUK’s Cancer Grand Challenges PROTECT & StandUp2Cancer cover developing iTAG2/CAR-T applications for at least two clinical trials in paediatric brain tumours investigating proprietary iTAG2-B7H3 CAR-T systems.
Patent Situation
A UK/GB priority was filed 7/11/2023, PCT/GB2023/052906 (WO2024100392A1) to cover the iTAG degron tag platform. CRH, ICR & UCLB are co-leading the commercialisation of iTAG. IPR for the CAR-T, such as b7-h3 binders; (WO2024009075A1, filed 4/07/2022) vest solely with UCL/UCLB.
Further Reading
- https://www.sciencedirect.com/science/article/pii/S2589004223011367
- https://pubmed.ncbi.nlm.nih.gov/40764385/
