Abstract 2383: The molecular binding mechanism of tislelizumab, an investigational anti-PD-1 antibody, is differentiated from pembrolizumab and nivolumab

Abstract

Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor expressed by activated T, B, and NK cells, which interacts with its ligand PD-L1/L2 to inhibit T-cell proliferation and effector functions such as tumor cell killing and cytokine production. Two anti-PD-1 antibodies approved by the FDA, pembrolizumab and nivolumab, have shown efficacy in many cancer types, nevertheless there are some indications where limited efficacy is observed. Tislelizumab (BGB-A317), an investigational anti-PD-1 antibody, has demonstrated significant clinical activity (85.7% ORR, including 61.4% CR) in relapsed/refractory classical Hodgkin’s lymphoma (R/R cHL). Additionally, tislelizumab is being studied in global pivotal trials in a number of malignancies, including non-small cell lung cancer, hepatocellular carcinoma, and esophageal squamous cell carcinoma. However, how tislelizumab binds to PD-1 has yet to be shown, particularly in comparison to pembrolizumab and nivolumab. Here we report the co-crystal structure of PD-1 extracellular domain and the Fab of tislelizumab. Tislelizumab interacts with IgV-like domain of PD-1 with an interface area of 1112 Å2. Structure-guided mutagenesis of PD-1 and surface plasmon resonance were performed to compare the binding of tislelizumab, pembrolizumab and nivolumab to mutant and wild type PD-1. The dissociation rate (kd) of tislelizumab from wild type PD-1 is about 100-fold and 50-fold slower than that of pembrolizumab and nivolumab, respectively. Gln75, Thr76, Asp77 and Arg86 on PD-1 are critical epitopes for tislelizumab, but mutation of them showed little effect on binding of PD-1 to pembrolizumab and nivolumab. Both the co-crystal structure and mutagenesis study identified the unique epitopes of tislelizumab that correlate to the extremely slow-off property of tislelizumab after binding to PD-1. In conclusion, we observed that tislelizumab is differentiated from pembrolizumab and nivolumab by its unique binding epitopes as well as binding kinetics. Citation Format: Yingcai Feng, Yuan Hong, Hanzi Sun, Bo Zhang, Hongfu Wu, Kang Li, Xuesong (Mike) Liu, Ye Liu. The molecular binding mechanism of tislelizumab, an investigational anti-PD-1 antibody, is differentiated from pembrolizumab and nivolumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2383.

A Phase 2 Study of Tislelizumab in Combination With Platinum-Based Chemotherapy as First-line Treatment for Advanced Lung Cancer in Chinese Patients

“…Tislelizumab is a monoclonal antibody with high affinity and specificity for PD-1 that was specifically engineered to minimize FcɣR binding on macrophages, thereby abrogating antibody-dependent phagocytosis, a potential mechanism of T-cell clearance and resistance to anti-PD-1 therapy [19]. Tislelizumab has shown higher affinity to PD-1 than pembrolizumab and nivolumab with an approximately 100and 50-fold slower off-rate, respectively [20]. Moreover, tislelizumab has a different binding orientation to PD-1 compared with pembrolizumab and nivolumab.…”

“…Moreover, tislelizumab has a different binding orientation to PD-1 compared with pembrolizumab and nivolumab. While the binding surface on PD-1 for tislelizumab partially overlaps with that for pembrolizumab, it significantly differs from that for nivolumab [20]. In two early phase studies, single-agent tislelizumab (200 mg) administered intravenously (IV) every 3 weeks (Q3W) was generally well tolerated and showed antitumor activity in both Caucasian and Asian patients [21,22].…”

Tislelizumab Plus Chemotherapy as First-line Treatment for Advanced Esophageal Squamous Cell Carcinoma and Gastric/Gastroesophageal Junction Adenocarcinoma

“…Tislelizumab is a humanized monoclonal antibody (mAb) with high affinity and specificity for PD-1 that was engineered to minimize binding to FcgR on macrophages to greatly reduce antibodydependent phagocytosis, a potential mechanism of T-cell clearance and resistance to anti-PD-1 therapy (19). Using structure-guided mutagenesis and Biacore studies, tislelizumab has been found to be structurally differentiated from both pembrolizumab and nivolumab by its unique binding epitopes and binding kinetics (20). In two earlyphase studies (NCT02407990, CTR20160872), tislelizumab (200 mg) administered intravenously every 3 weeks (Q3W) was generally well tolerated and demonstrated promising antitumor activity in both Asian and non-Asian patients with advanced solid tumors, including EC and GC (21,22).…”

Tislelizumab: an investigational anti-PD-1 antibody for the treatment of advanced non-small cell lung cancer (NSCLC)

“…Tislelizumab has a different binding orientation to PD-1 versus pembrolizumab and nivolumab; the binding surface on PD-1 for tislelizumab partially overlaps with that for pembrolizumab but differs significantly from that for nivolumab [33]. With a disassociation constant (K D ) of 0.15 nmol/L, tislelizumab binds to Gln75, Thr76, Asp77, and Arg86 of human PD-1 with high specificity and affinity [33,34].…”

“…Nivolumab and pembrolizumab do not require these epitopes to bind and have faster dissociation rates than tislelizumab. Tislelizumab has shown an approximately 50-fold and 100-fold slower dissociation rate compared with nivolumab and pembrolizumab, respectively [33]. Studies with pembrolizumab and nivolumab have demonstrated that maximal receptor occupancy on circulating CD3 + T cells occurs at concentrations that are much lower than the clinical dose for nivolumab and pembrolizumab [35,36].…”