Durable blockade of PD-1 signaling links preclinical efficacy of sintilimab to its clinical benefit

Abstract

Blockade of immune checkpoint pathways by programmed cell death protein 1 (PD-1) antibodies has demonstrated broad clinical efficacy against a variety of malignancies. Sintilimab, a highly selective, fully human monoclonal antibody (mAb), blocks the interaction of PD-1 and its ligands and has demonstrated clinical benefit in various clinical studies. Here, we evaluated the affinity of sintilimab to human PD-1 by surface plasmon resonance and mesoscale discovery and evaluated PD-1 receptor occupancy and anti-tumor efficacy of sintilimab in a humanized NOD/Shi-scid-IL2rgamma (null) (NOG) mouse model. We also assessed the receptor occupancy and immunogenicity of sintilimab from clinical studies in humans (9 patients with advanced solid tumor and 381 patients from 4 clinical studies, respectively). Sintilimab bound to human PD-1 with greater affinity than nivolumab (Opdivo®, MDX-1106) and pembrolizumab (Keytruda®, MK-3475). The high affinity of sintilimab is explained by its distinct structural binding mode to PD-1. The pharmacokinetic behavior of sintilimab did not show any significant differences compared to the other two anti-PD-1 mAbs. In the humanized NOG mouse model, sintilimab showed superior PD-1 occupancy on circulating T cells and a stronger anti-tumor effect against NCI-H292 tumors. The strong anti-tumor response correlated with increased interferon-γ-secreting, tumor-specific CD8+ T cells, but not with CD4+ Tregs in tumor tissue. Pharmacodynamics testing indicated a sustained mean occupancy of ≥95% of PD-1 molecules on circulating T cells in patients following sintilimab infusion, regardless of infusion dose. Sintilimab infusion was associated with 0.52% (2/381 patients) of anti-drug antibodies and 0.26% (1/381 patients) neutralizing antibodies. These data validate sintilimab as a novel, safe, and efficacious anti-PD-1 mAb for cancer immunotherapy.

Recent updates on Sintilimab in solid tumor immunotherapy

“…However, immunotherapy combined with anti-angiogenesis therapy presented a synergistic effect on the mechanism of action [23,46], which was proved by a trial of IMbrave 150 in unresectable HCC patients [23]. Strategies that combine other types of immunomodulators, chemotherapy, and molecular targeted treatments either in vivo or in vitro are ongoing [5].…”

Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11)

“…Compared with pembrolizumab or nivolumab, sintilimab has a different binding site and potentially greater affinity against PD-1 as per the preclinical data. 11 In a phase 1b study, sintilimab plus pemetrexed and platinum has been found to have tolerable safety profile and promising efficacy in previously untreated patients with nonsquamous NSCLC, with an objective response rate (ORR) of 68.4% and a median progression-free survival (PFS) of 11.4 months. 12 In this randomized, doubleblind, phase 3 study (ORIENT-11), we compared the combination of pemetrexed and platinum plus either sintilimab or a placebo in Chinese patients with locally advanced or metastatic nonsquamous NSCLC.…”

Safety and efficacy of sintilimab combined with oxaliplatin/capecitabine as first-line treatment in patients with locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma in a phase Ib clinical trial

“…It is safe to hypothesize that anti-PD-1 antibodies in combination with chemotherapy may further improve the clinical outcomes of patients with advanced GC. Sintilimab is a highly selective, monoclonal IgG4 antibody that inhibits interactions between PD-1 and its ligands, with strong anti-tumor response [ 23 ]. A phase 1a study for dose escalation, has demonstrated the tolerance and pharmacological activity of sintilimab in patients with advanced-stage solid tumors, but there is limited evidence for the efficacy of antibodies against PD-1 plus chemotherapy in Chinese G/GEJ adenocarcinoma patients.…”