Abstract C069: Toripalimab an anti-PD-1 antibody that demonstrates potent T cell activation and enhanced clinical efficacy irrespective of PD-L1 status

Abstract Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have revolutionized cancer treatment favoring prognostic benefits to a broad range of cancer patients. Currently, US Food and Drug Administration (FDA)–approved PD-1 monoclonal antibodies (mAbs) have demonstrated significant clinical benefit, particularly in patients with programmed cell death ligand 1 (PD-L1)-expressing tumors. Toripalimab is a PD-1 targeting humanized IgG4 mAb that is currently pending approval by the FDA as a first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). In combination with chemotherapy, toripalimab demonstrated significant clinical efficacy irrespective of PD-L1 status in patients in three different clinical trials, namely JUPITER-02 (NPC), JUPITER-06 (esophageal squamous cell carcinoma [ESCC]) and CHOICE-01 (non-small cell lung cancer [NSCLC]). Here we investigated the molecular and functional characteristics of toripalimab and compared it to pembrolizumab, a PD-1 mAb that is approved in the largest number of indications in the PD-1 mAb class. In comparison to pembrolizumab, toripalimab demonstrated a 12-fold higher binding affinity to PD-1 and selectively induced higher Th1 and myeloid derived inflammatory cytokine responses in human peripheral blood mononuclear cells (PBMCs). Upon treating dissociated tumor cells from treatment naïve NSCLC patients, toripalimab demonstrated an enhanced expression of several unique genes in interferon gamma and immune cell pathways compared to pembrolizumab. The binding of toripalimab to PD-1 ectopically expressed in Jurkat T cells, recruited lower levels of SHP1 and SHP2, the negative regulators of T cell activation, compared to pembrolizumab. Overall, our study demonstrates that toripalimab is differentiated from pembrolizumab in terms of stronger PD-1 binding, more potent in-vitro T cell activation and lower agonistic potential. These characteristics of toripalimab present it as a next generation PD-1 checkpoint inhibitor with potential for favorable clinical outcomes in treating cancer patients irrespective of their PD-L1 status. Citation Format: Xiaoguang Wang, Sruthi Ravindranathan, Daniel Chin, Su-Yi Tseng, Scott Klakamp, Kate Widmann, Varun Kapoor, Vladimir Vexler, Patricia Keegan, Sheng Yao, Sanjay D Khare, Theresa LaVallee, Narendiran Rajasekaran. Toripalimab an anti-PD-1 antibody that demonstrates potent T cell activation and enhanced clinical efficacy irrespective of PD-L1 status [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C069.