Development of an AchillesTAG degradation system and its application to control CAR-T activity

Therapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability

“…To investigate the therapeutic benefit whether loss of function of NUDT1 creates a MYC(N)-driven vulnerability, we employed proteolysis targeting chimera (PROTAC)-based technology to pharmacologically degrade NUDT1 protein, which in principle phenocopies the effects of gene knockout 17 . We noticed that C4 Therapeutics disclosed three selective, potent NUDT1 PROTAC degraders during the course of our study 18 . However, these degraders were rapidly metabolized in vivo, with half-life values < 0.8 h in pharmacokinetic (PK) studies.…”

Degron tagging for rapid protein degradation in mice

“…Although there is current interest in developing ligands against diverse E3 ligases, most PROTACs that have been developed, including those that target degron tags ( Bond et al, 2021 ; Nabet et al, 2018 , 2020 ; Nowak et al, 2021 ; Veits et al, 2021 ), recruit the cullin–RING E3 ligase (CRL) complexes CRL2 VHL and CRL4A CRBN . This has been driven by ligand availability, the broad expression of these complexes across cell types ( Uhlén et al, 2015 ) and their ability to degrade diverse neo-substrates.…”

“…However, the development of potent and selective degraders for new protein targets remains costly and time consuming, particularly for compounds destined for the clinic, which often require extensive optimisation to achieve desirable pharmacokinetic properties ( Pike et al, 2020 ). An alternative approach leverages both genome editing and protein engineering (see poster, ‘Degron tagging via chemically induced E3 ligase proximity’) to fuse additional peptide sequences to target proteins (hereafter referred to as ‘degron tags’) that interact with E3 ubiquitin ligases in a chemically controllable manner ( Bond et al, 2021 ; Bouguenina et al, 2023 ; Carbonneau et al, 2021 ; Nabet et al, 2018 , 2020 ; Nishimura et al, 2009 ; Nowak et al, 2021 ; Veits et al, 2021 ; Yamanaka et al, 2020 ). This renders the degron-tagged protein susceptible to degradation using generic pre-validated degrader molecules, over time scales of minutes to hours, in a manner that is reversible and dosage controllable.…”

Targeted Protein Degradation: Clinical Advances in the Field of Oncology

“…Furthermore, Veits et al recently reported a novel degradation methodology on fusing a POI to the small protein MTH1 (MutT homolog-1), which serves as a ligand-binding tag [ 78 ].This AchillesTag (aTAG) can be paired with different heterobifunctional degraders that recruit the CRBN E3 ligase into close proximity, leading to ablation of any aTAG-fused POI ( Figure 9 b). Proof of principle has been provided by selectively controlling Chimeric Antigen Receptor (CAR) protein levels [ 78 ]. Treatment with aTAG degraders attenuated CAR-mediated target tumor cell killing and T-cell activation/cytokine release.…”

“…Six CAR-T cell products are already in the market for the treatment of B-cell acute lymphoblastic leukemia, lymphomas and multiple myeloma: Kymriah (Tisagenlecleucel), Yescarta (Axicabtagene ciloleucel), Tecartus (Brexucabtagene autoleucel), Breyanzi (Lisocabtagene maraleucel), Abecma (Idecabtagene vicleucel) and Carvykti (Ciltacabtagene autoleucel). However, these therapies have been associated with unique adverse events including cytokine-release syndrome, neurologic events and immune effector cell-associated neurotoxicity [ 78 , 79 ]. Therefore, fine tuning of protein expression in CAR-T therapy provides clinical benefit.…”