Abstract 4245: QL301, a PD-L1 dependent 4-1BB agonist with enhanced preclinical anti-tumor efficacy and minimal liver toxicity

Abstract

4-1BB (CD137, TNFRSF9) is a potent co-stimulatory receptor found on T and NK cells. Activation of 4-1BB requires receptor clustering, which is naturally mediated by the endogenous trimeric 4-1BB ligand. Cross-linking via agnostic monoclonal antibodies can also activate 4-1BB but has generally resulted in unwanted side effects, mainly liver toxicity. To address the shortcomings of 4-1BB agonists, we have developed QL301, a PD-L1 x 4-1BB bispecific antibody that conditionally activates 4-1BB only when concurrently engaged to PD-L1, an immune checkpoint mediator elevated in the immuno-suppressive tumor microenvironment. The IgG1 backbone of QL301 was mutated to eliminate Fc gamma receptor-dependent functions such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), thereby preventing depletion of effector immune cells and non-specific activation of 4-1BB through Fc gamma receptor binding. In addition, QL301 blocks the suppressive interaction of PD-1 with PD-L1. Therefore, through a combination of 4-1BB agonism and PD-L1 blockade, QL301 provides both a co-stimulatory signal and the release of a suppressive signal to reinvigorate anti-tumor immune response. In vitro, QL301 induced robust cytokine release and expansion of CD8+ T cells conditional on the presence of tumor or antigen presenting cells expressing PD-L1. In xenograft and transgenic mice models, QL301 had potent anti-tumor effect that was superior to PD-L1 monoclonal antibodies. Tumor regression correlated with the expansion of CD8+ T cells. In addition, QL301 potentiated tumor cell killing mediated by an EGFR targeted CD3 bispecific antibody, providing a basis for combination therapy. In non-human primates, QL301 was well tolerated up to 30 mg/kg. There was no chronic elevation of serum AST and ALT levels, and histopathology analysis showed minimal inflammation of liver tissue. A phase 1 clinical trial to evaluate the safety, tolerability, and early efficacy of QL301 is currently ongoing. Citation Format: Shenda Gu, Irene Tang, Shirley Mihardja, Wei Wei Prior, Hieu V. Tran, Allan Chan, Anna McClain, Aaron Kurtzman, Shihao Chen, Youguang Luo, Xiaoyan Kang, Xiaoran Wu, Qingmei Zheng, Guodong Jia. QL301, a PD-L1 dependent 4-1BB agonist with enhanced preclinical anti-tumor efficacy and minimal liver toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4245.