Toripalimab, a therapeutic monoclonal anti-PD-1 antibody with high binding affinity to PD-1 and enhanced potency to activate human T cells

Abstract

Over the past decade, US Food and Drug Administration (FDA)-approved immune checkpoint inhibitors that target programmed death-1 (PD-1) have demonstrated significant clinical benefit particularly in patients with PD-L1 expressing tumors. Toripalimab is a humanized anti-PD-1 antibody, approved by FDA for first-line treatment of nasopharyngeal carcinoma in combination with chemotherapy. In a post hoc analysis of phase 3 studies, toripalimab in combination with chemotherapy improved overall survival irrespective of PD-L1 status in nasopharyngeal carcinoma (JUPITER-02), advanced non-small cell lung cancer (CHOICE-01) and advanced esophageal squamous cell carcinoma (JUPITER-06). On further characterization, we determined that toripalimab is molecularly and functionally differentiated from pembrolizumab, an anti-PD-1 mAb approved previously for treating a wide spectrum of tumors. Toripalimab, which binds the FG loop of PD-1, has 12-fold higher binding affinity to PD-1 than pembrolizumab and promotes significantly more Th1- and myeloid-derived inflammatory cytokine responses in healthy human PBMCs in vitro. In an ex vivo system employing dissociated tumor cells from treatment naïve non-small cell lung cancer patients, toripalimab induced several unique genes in IFN-γ and immune cell pathways, showed different kinetics of activation and significantly enhanced IFN-γ signature. Additionally, binding of toripalimab to PD-1 induced lower levels of SHP1 and SHP2 recruitment, the negative regulators of T cell activation, in Jurkat T cells ectopically expressing PD-1. Taken together, these data demonstrate that toripalimab is a potent anti-PD-1 antibody with high affinity PD-1 binding, strong functional attributes and demonstrated clinical activity that encourage its continued clinical investigation in several types of cancer.

The combination of immune checkpoint inhibitors and antibody-drug conjugates in the treatment of urogenital tumors: a review insights from phase 2 and 3 studies

“… [ 57 ] KEYNOTE-361 3 1010 aUC Pemb PD-1 PFS changed little; mPFS: 8.3 m vs. 7.1 m; mOS: 17.0 m vs. 14.3 m. [ 58 ] POLARIS-03 2 151 mUC Tori PD-1 ORR: 26% with a DCR of 45%; mDR, PFS, and OS: 19.7 m, 2.3 m, and 14.4 m. [ 59 ] NCT02527434 2 32 la/mUC Tori PD-1 ORR:18.8%, including CR: 6.3%, and PR: 12.5%. [ 60 ] CheckMate 275 2 270 mUC Nivo PD-1 mOS:7.0 m. [ 61 ] SWOGS1605 2 172 NMIBC Atez PD-L1 27% experienced a CR at 6.0 m; mDR: 17.0 m. [ 63 ] IMvigor 211 3 127 la/mUC Atez PD-L1 mOS: 9.2 m vs. 7.7 m. [ 64 ] IMvigor 210 2 123 la/mUC Atez PD-L1 ORR: 23%; CRR: 9%; mOS: 15.9 m. [ 65 ] IMvigor130 3 1213 la/mUC (A)Atez+C; (B)Atez; (C)C PD-L1 + C mPFS: 8.2 m(A), 6.3 m(C); mOS: 16.0 m(A), 13.4 m(C); mOS: 15.7 m(B). [ 66 ] NCT02792192 2 24 NMIBC Atez + BCG PD-L1 + Immune targets Atez + BCG was well-tolerated.…”

“…It is worth noting that toripalimab has a high affinity for PD-1 (approximately 23 times that of pembrolizumab and 35 times that of nivolumab), which exerts a powerful and durable pathway blocking the disruption effect after binding [ 64 ]. In addition, toripalimab also undergoes stronger endocytosis than pembrolizumab and nivolumab, which can effectively reduce the expression of PD-1 on the cell membrane, so as to further enhance the PD-1 expression band, inhibit immunity, and promote “immune normalization” of tumors [ 65 ].…”