In recent years, the research into immune checkpoint inhibitors has facilitated the rapid development of tumour immunotherapy. Immune checkpoints are crucial proteins in maintaining the immune response and protecting normal tissues. Nevertheless, these molecules may also be exploited by tumour cells to evade immune surveillance[1-3]. Immune checkpoint inhibitors represented by anti-PD-1/L1 antibodies can restore the immune system's anti-tumour activity by blocking the binding of immune checkpoints to their ligands, and have been widely used for the treatment of various types of malignant tumuors[4]. Serplulimab (HANSIZHUANG) is a recombinant humanised anti-PD-1 mAb injection independently developed by Henlius, and the world's first anti-PD-1 mAb approved for the first-line treatment of small cell lung cancer (SCLC). Up to date, HANSIZHUANG has been approved by China’s National Medical Products Administration for the treatment of microsatellite instability-high (MSI-H) solid tumours, squamous non-small cell lung cancer (sqNSCLC), extensive-stage small cell lung cancer (ES-SCLC), and esophageal squamous cell carcinoma (ESCC), benefiting approximately 80,000 patients.
Based on its outstanding therapeutic efficacy in the treatment of small cell lung cancer (SCLC), serplulimab has became the world's first anti-PD-1 mAb approved for the treatment of SCLC. According to related research results, serplulimab targeted against a similar binding epitope compared with that targeted by pembrolizumab, while the spatial organisation of the heavy and light chains of serplulimab is unique, which may contribute to the different spatial interaction between serplulimab and PD-1 receptor. Moreover, due to its unique mode of recognition, serplulimab exhibits higher affinity (KD=2.42 nM) than other PD-1 inhibitors and robustly induces PD-1 receptor endocytosis, resulting in reduction of PD-1 receptors retained on the surface of T cells[5]. To further investigate the molecular mechanism of serplulimab, researchers analysed the expression level of key modulators on PD-1/L1 signalling pathway. The results showed that, serplulimab reduced the recruitment of immune co-stimulatory receptor CD28 by PD-1, thereby decreasing the dephosphorylation of CD28 mediated by phosphatase SHP2 and retaining the signal transmitted by CD28[6-8]. Further downstream the signalling pathway, the activity of protein kinase AKT was enhanced[9], thereby promoting sustained activation of T cells.
Moreover, the researchers examined the anti-tumour activity of a PD-1 inhibitor, such as serplulimab or pembrolizumab, in combination with another immune checkpoint inhibitor. The results suggest that compared with serplulimab alone, combined treatment with serplulimab/HLX53 (anti-TIGIT Fc protein) resulted in dual PD-1/L1-TIGIT blockade and greater tumour growth inhibition(TGI) and survival rate reduction. Also, the serplulimab/HLX53 combination demonstrated higher potential as an immunotherapy compared with pembrolizumab/HLX53. Specifically, serplulimab/HLX53 significantly promoted the infiltration of effector CD4+ T cells and effector CD8+ T cells within tumours versus pembrolizumab/tiragolumab (an anti-TIGIT mAb). In addition, a series of analysis and data suggest that serplulimab/HLX53 induced strong modulation on the tumour microenvironment, mobilising immune cells to turn “cold” tumours into “hot” ones to improve the efficacy of anti-tumour immunotherapy (SCLC is often considered an immune-cold tumour). In addition, the serplulimab/HLX26 combination also enhanced anti-tumour activity compared with their respective monotherapies, which may further amplify the therapeutic advantages of serplulimab as an immune cornerstone product.
Looking forward, Henlius will further expand HANSIZHUANG’s differentiated and multi-dimensional layout underpinned by the patient-centric strategy. Meanwhile, the company will actively promote HANSIZHUANG in combination with in-house products of Henlius and chemotherapy drugs to conduct immune combination therapies in a wide variety of indications, committing to bringing affordable and high-quality innovative treatments to patients around the world.
Reference
1. Ai L, et al. Roles of PD-1/PD-L1 Pathway: Signaling, Cancer, and Beyond. Adv Exp Med Biol. 2020; 1248:33-59.
2. Latchman Y, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261-268.
3. Dong H, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion [published correction appears in Nat Med 2002 Sep;8(9):1039]. Nat Med. 2002;8(8):793-800.
4. Curran MA. Preclinical Data Supporting Antitumor Activity of PD-1 Blockade. Cancer J. 2018;24(1):2-6.
5. Issafras H, et al. Structural basis of HLX10 PD-1 receptor recognition, a promising anti-PD-1 antibody clinical candidate for cancer immunotherapy. PLoS One. 2021;16(12):e0257972.
6. Hui E, et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science. 2017;355(6332):1428-1433.
7. Patsoukis N, et al. Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation. Commun Biol. 2020;3(1):128.
8. Fenwick C, et al. Tumor suppression of novel anti-PD-1 antibodies mediated through CD28 costimulatory pathway. J Exp Med. 2019;216(7):1525-1541.
9. Primavera E, et al. Computer-Aided Identification of Kinase-Targeted Small Molecules for Cancer: A Review on AKT Protein. Pharmaceuticals (Basel). 2023;16(7):993.
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