Golcadomide demonstrates potent antiproliferative activity in T-cell lymphoma via degradation of IKZF1 and IKZF3

Abstract T-cell lymphomas (TCLs) are a heterogeneous group of aggressive non-Hodgkin lymphomas characterized by poor prognosis and limited treatment options. The aggressive biology, molecular diversity, and resistance to conventional treatments underscore a critical unmet need for novel, targeted therapeutic strategies. Golcadomide is a potential first-in-class, oral CELMoDTM agent designed for the treatment of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. Golcadomide drives the closed, active conformation of cereblon to induce rapid and deep degradation of IKZF1 and IKZF3, leading to direct cell killing and immunomodulatory activity. Previous studies were largely focused on B cell lymphoma. In this study, we test the in vitro activity of golcadomide and evaluate its potential as a therapeutic agent for patients with T-cell lymphoma. The antiproliferative and pro-apoptotic activity of golcadomide was evaluated in a panel of 10 TCL cell lines, including adult T-cell leukemia/lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), and anaplastic large cell lymphoma (ALCL). Cell lines were treated with increasing concentrations of golcadomide or lenalidomide and cell viability and apoptosis were assessed over nine days. All cell lines exhibited greater sensitivity to golcadomide than to lenalidomide, with golcadomide producing enhanced inhibition of proliferation and stronger induction of apoptosis. Importantly, all TCL subtypes tested responded to golcadomide, supporting its potential as a broadly active therapeutic agent. To characterize golcadomide-induced protein degradation, proteomic mass spectrometry was performed in four TCL cell lines. Golcadomide demonstrated statistically significant and dose-responsive downregulation of the neo-substrates IKZF1 and IKZF3. Extended treatment confirmed that golcadomide elicited both dose- and time-dependent changes in the T-cell lymphoma proteome, while lenalidomide produced minimal effects across these models. The degradation of IKZF1 and IKZF3 by golcadomide was further validated in an expanded panel of TCL cell lines with immunoblot and flow cytometry analyses. Regardless of baseline expression levels, golcadomide treatment resulted in robust degradation of IKZF1 and IKZF3, which was notably more pronounced than with lenalidomide. Specifically, golcadomide induced nearly complete IKZF1 and approximately 80% IKZF3 degradation in ATL-3I and MT-2 cells after 24 hours, while lenalidomide treatment achieved only about 40% degradation for both proteins. To determine the substrates necessary for golcadomide's antiproliferative effects, TCL cell lines expressing non-degradable mutant forms of IKZF1 or IKZF3 were generated. Overexpression of these mutants effectively protected the cells from golcadomide-induced antiproliferation in all tested models and also conferred resistance against lenalidomide in lenalidomide-sensitive cell lines. In summary, these findings support the continued development of golcadomide as a promising therapeutic for T-cell lymphomas. Its potent efficacy across multiple TCL subtypes and mechanisms involving IKZF1 and IKZF3 degradation highlight a novel strategy to address unmet clinical need in this challenging disease.