CFT7455: A NOVEL, IKZF1/3 DEGRADER THAT DEMONSTRATES POTENT TUMOR REGRESSION IN A SPECTRUM OF NHL XENOGRAFT MODELS

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Introduction: Ikaros family zinc finger protein 1 and 3 (IKZF1/3) are essential transcription factors (TF) for differentiation of B and T lymphocytes. IMiDs (e.g. pomalidomide (pom)) degrade IKZF1/3 via interaction with the cereblon (CRBN) E3 ligase and have shown promise in NHL. Preclinical data suggest improvements in IKZF1/3 degraders may lead to enhanced efficacy. CFT7455 is a novel IKZF1/3 degrader optimized for high affinity CRBN binding and IKZF1/3 degradation, resulting in downregulation of the interferon regulatory factor 4 (IRF4), a critical regulator in non-Hodgkin's lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and peripheral T-cell lymphoma (PT). Methods: Protein expression in cell lines and tumor xenografts were quantified by immunoassays or targeted mass spectrometry. Binding affinity was determined by fluorescence polarization or cellular NanoBRET assays. Cell viability were monitored by CellTiter-Glo. Tumor xenograft studies were conducted by implanting human NHL lines into immunocompromised mouse strains. Results: CFT7455's potency as a CRBN binder is evident from cellular CRBN competition studies (IC50 = 0.4 nM). In the ALK+ anaplastic large cell lymphoma (ALCL) line KiJK, CFT7455 treatment led to >80% degradation of IKZF1, which was blocked by proteasome or NEDD8 inhibition, demonstrating on mechanism activity. CFT7455 demonstrated potent antiproliferative activity across a panel of NHL cell lines. In KiJK xenografts, pom treatment was ineffective at a clinically relevant dose (3000 µg/kg/day). CFT7455 treatment (100 µg/kg/day, PO) resulted in durable tumor regression associated with deep IKZF3 degradation and IRF4 downregulation (7% and 25% remaining, respectively). CFT7455 showed dose dependent efficacy in the ALK- ALCL xenograft model, DL40, from 3-100 µg/kg with regressions at doses ≥10 µg/kg. Global proteomic studies on DL40 xenografts treated with CFT7455 (100 µg/kg, 4 hours) showed only IKZF1/3 were significantly degraded. MCL is characterized by elevated cyclin D1, subsequent release of E2F1 and pathway activation. In the REC1 MCL xenograft model, doses of CFT7455 ≥10 µg/kg promoted tumor regression. Pharmacodynamic studies showed that CFT7455 (30 µg/kg) promoted degradation of IKZF3 and downregulation of cyclin D1 and E2F1. In a pom insensitive DLBCL model (TMD8), administration of CFT7455 (100 µg/kg) led to tumor regression. Together these results show that the optimized CRBN binding and catalytic activity of CFT7455 results in rapid, deep and sustained degradation of IKZF1/3 and translates to tumor regressions in NHL models. Conclusions: CFT7455 is a potent, selective catalytic degrader of IKZF1/3, with single agent antitumor activity in DLBCL, ALCL, and MCL models including those insensitive to pom. These results support clinical investigation of CFT7455 for NHL. Keywords: Molecular Targeted Therapies, Aggressive B-cell non-Hodgkin lymphoma, Aggressive T-cell non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract S. Perino Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics B. Class Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics C. Henderson Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics M. Isasa Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics R. J. Kirby Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics R. V. Agafonov Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics P. Chaturvedi Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics S. J. Eron Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics A. Good Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics A. A. Hart Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics J. A. Henderson Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics B. T. Kreger Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics M. Mahler Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics R. M. Pollock Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics A. S. Crystal Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics C. G. Nasveschuk Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics S. L. Fisher Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics D. A. Proia Employment or leadership position: C4 Therapeutics Stock ownership: C4 Therapeutics

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