SB-4826 / Oncovalent Therap - LARVOL DELTA

Metabolic Reprograming of Exhausted Intratumoral CD8+ T-Cell Underlies Anti-Tumor Activity of Sumoylation Inhibitors in Large B Cell Lymphoma (ASH 2023) - "Here we show, using a syngeneic model of LBCL, that PD1 resistance is associated with lower CD8+ T-cell basal metabolic rate (BMR) in tumor infiltrating lymphocytes (TIL), and that treatment with the covalent SUMOylation inhibitor (SB-4826) increases the metabolic rate of TIL by metabolic reprograming...Cell 2007). We hypothesize that metabolic reprograming of CD8 T-cells through increased HIF-1a is the basis for synergy between SUMOylation inhibition and immune checkpoint inhibitors in LBCL."

B Cell Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Large B Cell Lymphoma • Lymphoma • Metabolic Disorders • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Targeted Protein Degradation • CD4 • CD8 • HAVCR2 • HIF1A

Inhibition of SUMOylation reverses T-cell metabolic exhaustion in large B-cell lymphoma (AACR 2025) - "Inhibitors of SUMOylation (SUMOi) have shown anti-tumor activity in a CD8 T-cell dependent manner, however, the mechanism behind this T-cell dependence is unknown.We show that a novel covalent SUMOi, SB-4826 leads to a robust anti-tumor response which is dependent on CD8+ T-cells in lymphoma...We found that multiple T-cell transcriptional regulators, including TBET, LEF1 and TCF1 are all SUMOylated either during a resting or activation state in CD8+ T-cells. Together, these findings suggest a novel role for SUMOylation in regulating T-cell effector activation and exhaustion, by modulating metabolic state likely through the regulation of key transcriptional T-cell programs."

B Cell Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • CD8 • PD-1

SB-4826, a first-in-class oral, covalent inhibitor of SUMO E1 that induces IFN signaling and inhibits tumor growth as monotherapy and in combination with immune checkpoint blockade (AACR 2023) - "In a human RAJI xenograft model, SB-4826 induced near-complete inhibition of tumor growth as a single agent and resulted in tumor regression when combined with rituximab...SUMO E1 is a clinically validated cancer target as evidenced by recent data showing encouraging responses to TAK-981, an IV-administered, ATP-competitive inhibitor. SB-4826 is a differentiated and optimized SUMO E1 inhibitor that is administered orally and demonstrated improved activity in preclinical models. SB-4826 has favorable properties for development, is a new and promising cancer therapy, and is entering phase 1 clinical studies in 2023."

Checkpoint block • Checkpoint inhibition • Combination therapy • IO biomarker • Late-breaking abstract • Monotherapy • Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor • CD8