Abstract 1912: Targeting Trop-2 with sacituzumab govitecan (IMMU-132) suppresses the tumor growth in diffuse large B cell lymphoma

Abstract

Abstract Introduction: Sacituzumab govitecan (SG), also termed IMMU-132, is an antibody-drug conjugate, linking an anti-Trop-2 antibody and the topoisomerase I inhibitor, SN-38. Clinically, SG has shown promising therapeutic effects in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. However, the efficacy of SG in diffuse large B-cell lymphoma (DLBCL) remains unexplored. In this study, we sought to determine whether SG can efficiently inhibit cell proliferation and tumor growth of DLBCL by using both in vitro and in vivo models. Methods: We examined the cytotoxicity of SG in the activated B-cell like (ABC)-subtype-DLBCL cell lines, Riva (Ri-1), HBL-1, and SU-DHL-2, and the germinal center B-cell (GCB)-subtype-DLBCL cell lines, SU-DHL-4, SU-DHL-5, and SU-DHL-6 by MTT assay. We assessed the distributions of cell cycle phase and apoptosis in the aforementioned DLBCL cell lines treated with SG for 24 h or 48 h using flow cytometry and Annexin V staining. We confirmed apoptosis (cleavage of poly ADP-ribose polymerase [PARP] and caspase-3) and detected DNA damage (γH2AX and 53BP1)-related protein expression in SU-DHL-2 and SU-DHL-6 cell lines treated with SG at various concentrations for 48 h using western blotting, compared to untreated cells. To examine the anti-tumor effect of SG in vivo, NOD-SCID nude mice of Riva-xenograft mouse models were randomized into a control group and an SG-treated group. Results: Flow cytometry and western blotting revealed overexpression of Trop-2 on the surface of untreated ABC-DLBCL and GCB-DLBCL cell lines. In this study, we showed that SG treatment reduced cell viability in all six DLBCL cell lines with nanomolar IC50 values. Exposing SG to DLBCL cells significantly increased cell cycle arrest at the G2/M and sub-G1 phases of all six DLBCL cell lines. Annexin V staining revealed that SG induced apoptosis in all six DLBCL cell lines. Western blotting confirmed apoptosis induction by showing a dose-dependent upregulation of cleaved PARP and cleaved caspases-3 by SG treatment, along with decreased expression of survivin in both SU-DHL-2 and SU-DHL-6 cells. SG also upregulated the expression of γH2AX and 53BP1 in both SU-DHL-2 and SU-DHL-6 cells. Furthermore, we found that tumor growth of Riva cells in vivo was significantly reduced by treatment with SG when compared with untreated control. Conclusion: SG suppresses tumor growth of ABC-DLBCL and GCB-DLBCL cells in both in vitro and in vivo models by inducing cell cycle arrest, apoptosis, and DNA damage. These findings provide a rationale for transitioning SG to clinical trials for treating patients with relapsed or refractory DLBCL. Citation Format: Jakie Ting, Ming-Feng Wei, Hsiao-Wei Lee, Keng-Hsueh Lan, Ann-Lii Cheng, Sung-Hsin Kuo. Targeting Trop-2 with sacituzumab govitecan (IMMU-132) suppresses the tumor growth in diffuse large B cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1912.