CC‐99282 IS A NOVEL CEREBLON E3 LIGASE MODULATOR (CELMOD) AGENT WITH POTENT AND BROAD ANTITUMOR ACTIVITY IN PRECLINICAL MODELS OF DIFFUSE LARGE B‐CELL LYMPHOMA (DLBCL) (2021)

Introduction: CC-99282 is an Ikaros- and Aiolos-targeting oral CELMoD agent in development for the treatment of relapsed/refractory non-Hodgkin lymphomas (R/R NHL). While patients with R/R NHL tend to have poor prognoses, agents mediating Ikaros/Aiolos degradation, such as lenalidomide (LEN) and avadomide (AVA), have shown promise in the R/R NHL setting. Methods: The effects of CC-99282 were studied in lymphoma and nontumorigenic human cell lines, primary cells, and lymphoma xenograft models. Shotgun proteomics, immunoblotting, enzyme fragment complementation assays, and flow cytometry studies assessed substrate degradation selectivity of CC-99282. CRISPR/Cas9 gene editing was performed in lymphoma cell lines and a T-cell restimulation assay evaluated immune-stimulatory effects. Results: CC-99282 demonstrated potent autonomous cell killing and apoptosis in DLBCL cells, independent of the origin subtype, presence of high-risk chromosomal translocations, or acquired resistance to doxorubicin. Of 23 cell lines tested, 20 showed sensitivity to CC-99282 with IC50 of 1–500 nM; similar low IC50 values were achieved only in 3 cell lines treated with AVA and none with LEN. No general cytotoxicity was observed in nontumorigenic cells in culture treated with ≤10 µM of CC-99282. While genetic knockout of either IKZF1/Ikaros or IKZF3/Aiolos sensitized DLBCL cells, the expression of degradation-resistant mutants of Ikaros/Aiolos protected them from the antiproliferative effects of CC-99282. The deep and sustained degradation of Ikaros/Aiolos in DLBCL cells treated with CC-99282 correlated with: the induction of interferon (IFN)-inducible genes (IRF7, IFIT3, and DDX58); a reduction of the highly critical oncogenic factors c-Myc and IRF4; and the induction of cleaved caspases and PARP. Several DLBCL xenograft models treated with CC-99282 (1–30 mg/kg) at different dosing schedules showed significant (P < 0.0001) tumor regression and tumor-free status (Figure). The strong antitumor activity was accompanied with robust distribution of CC-99282 across multiple tissues, including effectively crossing the blood-brain barrier in the intracranial xenograft model of central nervous system lymphoma. Degradation of Ikaros/Aiolos by CC-99282 in T cells correlated with increased secretion of IL-2, a hallmark of immune activation. CC-99282 was able to reverse T-cell exhaustion and induce secretion of the effector cytokines/chemokines GM-CSF, IFNγ, and TNFα, at concentrations (0.1–100 nM) that induced strong antitumor effects in vitro. The research was funded by: Bristol Myers Squibb Keywords: Molecular Targeted Therapies Conflicts of interests pertinent to the abstract A. Lopez-Girona Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb L. Groocock Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb Z. Mo Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb R. K. Narla Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb P. Janardhanan Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb S. Wood Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb D. Mendy Employment or leadership position: Bristol Myers Squibb L. Barnes Employment or leadership position: Bristol Myers Squibb S. Peng Employment or leadership position: Bristol Myers Squibb D. Jankeel Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb C. Fontanillo Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb S. Carrancio Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb J. Hansen Employment or leadership position: Bristol Myers Squibb