Structural basis of HLX10 PD-1 receptor recognition, a promising anti-PD-1 antibody clinical candidate for cancer immunotherapy

Abstract

Cancer immunotherapies, such as checkpoint blockade of programmed cell death protein-1 (PD-1), represents a breakthrough in cancer treatment, resulting in unprecedented results in terms of overall and progression-free survival. Discovery and development of novel anti PD-1 inhibitors remains a field of intense investigation, where novel monoclonal antibodies (mAbs) and novel antibody formats (e.g., novel isotype, bispecific mAb and low-molecular-weight compounds) are major source of future therapeutic candidates. HLX10, a fully humanized IgG4 monoclonal antibody against PD-1 receptor, increased functional activities of human T-cells and showed in vitro, and anti-tumor activity in several tumor models. The combined inhibition of PD-1/PDL-1 and angiogenesis pathways using anti-VEGF antibody may enhance a sustained suppression of cancer-related angiogenesis and tumor elimination. To elucidate HLX10’s mode of action, we solved the structure of HLX10 in complex with PD-1 receptor. Detailed epitope analysis showed that HLX10 has a unique mode of recognition compared to the clinically approved PD1 antibodies Pembrolizumab and Nivolumab. Notably, HLX10’s epitope was closer to Pembrolizumab’s epitope than Nivolumab’s epitope. However, HLX10 and Pembrolizumab showed an opposite heavy chain (HC) and light chain (LC) usage, which recognizes several overlapping amino acid residues on PD-1. We compared HLX10 to Nivolumab and Pembrolizumab and it showed similar or better bioactivity in vitro and in vivo, providing a rationale for clinical evaluation in cancer immunotherapy.

Effect of First-Line Serplulimab vs Placebo Added to Chemotherapy on Survival in Patients With Extensive-Stage Small Cell Lung Cancer

“…Serplulimab exhibited a higher affinity to human PD-1 than nivolumab and pembrolizumab, as well as a greater potency to block PD-L1 and PD-L2 signaling than nivolumab . In the in vivo models, serplulimab inhibited tumor growth at a lower dose than nivolumab . The mechanisms underlying the better survival outcome with serplulimab remain unknown, while the preclinical findings provide directions for future studies.…”

“…Serplulimab binds to different epitopes in PD-1 compared with nivolumab and pembrolizumab . Serplulimab exhibited a higher affinity to human PD-1 than nivolumab and pembrolizumab, as well as a greater potency to block PD-L1 and PD-L2 signaling than nivolumab .…”

Hsa_hsa_circ_0081069 promotes the progression of colorectal cancer through sponging miR‐665 and regulating E2F3 expression

“…Additionally, functional assays demonstrated that hsa_circ_0081069 silencing impaired cell proliferation, migration and invasion, as well as the angiogenic potential of CRC cells, indicating that hsa_circ_0081069 serves as an indispensable oncogenic factor in CRC. Angiogenesis is an important process for tumor growth and metastasis 37,38 . The growth and survival of a rapidly‐growing tumor population depends on neovascularization to supply oxygen and nutrients 39 .…”

“…Angiogenesis is an important process for tumor growth and metastasis. 37 , 38 The growth and survival of a rapidly‐growing tumor population depends on neovascularization to supply oxygen and nutrients. 39 As Qian et al showed, miR‐143 suppresses the proliferation and angiogenesis in CRC, which promotes the chemosensitivity to oxaliplatin administration.…”

First-line serplulimab or placebo plus chemotherapy in PD-L1-positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial

“…Serplulimab (HLX10) is a fully humanized, selective immunoglobulin G4 monoclonal antibody against PD-1 receptor 17 . Serplulimab showed promising antitumor activity and a manageable safety profile in various tumor types in phase 2 clinical trials 18 , 19 .…”