Recently, the preclinical study results and molecular characteristics of Henlius’ innovative anti-PD-1 monoclonal antibody (mAb) serplulimab (HLX10) were published in PLOS ONE. The results showed that compared to nivolumab and pembrolizumab, serplulimab showed similar or better bioactivity in vitro and in vivo and anti-tumor activity in several tumour models. Furthermore, serplulimab synergizes with bevacizumab biosimilar 汉贝泰 (HLX04) to promote robust tumour activity. Detailed epitope of the antigen-binding fragment (Fab) of serplulimab in complex with PD-1 analysis showed that serplulimab has a unique mode of recognition compared to the clinically approved PD-1 antibodies pembrolizumab and nivolumab with a similar binding epitope region to pembrolizumab.
Serplulimab, a fully humanized IgG4 mAb against PD-1 receptor, increased functional activities of human T-cells. The in vitro study showed that serplulimab activates T-cell proliferation and activization. The in vivo study showed anti-tumour efficacy in several tumour models. Serplulimab showed anti-tumour efficacy similar to nivolumab in non-small cell lung cancer (NSCLC) tumour model and pembrolizumab in triple-negative breast cancer (TNBC) tumour model. The combined inhibition of PD-1/PD-L1 and angiogenesis pathways using bevacizumab HLX04 may enhance a sustained suppression of cancer-related angiogenesis and tumour elimination, and serplulimab showed favorable tumour suppressive efficacy both in colorectal cancer (CRC) and NSCLC tumour models. The results laid foundation to the clinical trials of serplulimab in combination with HLX04. To gain insight into how serplulimab achieves PD-1 recognition, scientists determined the co-crystal structure of the Fab of serplulimab in complex with PD-1 and compared this structure to the previously determined structures of pembrolizumab and nivolumab. Compared to the clinically approved PD-1 antibodies pembrolizumab and nivolumab, serplulimab has a similar binding epitope region to pembrolizumab. Serplulimab and pembrolizumab showed an opposite heavy chain (HC) and light chain (LC) usage. Serplulimab interface occupies a solvent-accessible overlapping surface area of 445Å2 (55% of PD-L1 surface) on PD-1.
Henlius has adopted a differentiated "Combo+Global" strategy on serplulimab. Currently, serplulimab has been approved for clinical trials in China, the United States, the European Union and other countries and regions. A total of 10 immuo-oncology therapies clinical trials of serplulimab are ongoing to evaluate its safety and efficacy in a wide variety of solid tumors that cover lung cancer, hepatocellular carcinoma, esophageal carcinoma, head and neck squamous cell carcinoma and gastric cancer etc. In April, the New Drug Application (NDA) of serplulimab for the treatment of MSI-H solid tumours was accepted by the NMPA and granted priority review. It is expected to be approved in the first half of 2022. In the field of first-line treatment of lung cancer, the NDA of serplulimab combined with chemotherapy in locally advanced or metastatic squamous non-small cell lung cancer was accepted by NMPA in September. The international multi-center Phase 3 study of serplulimab in combination with chemotherapy in previously untreated extensive small-cell lung cancer recently reached the primary endpoint. Henlius will proceed to file the regulatory applications for this indication as soon as possible. It is expected to be the first anti-PD-1 mAb for first-line treatment of SCLC.
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Reference
Issafras H, Fan S, Tseng C-L, Cheng Y,
Lin P, Xiao L, et al. (2021) Structural basis of HLX10 PD-1 receptor
recognition, a promising anti-PD-1 antibody clinical candidate for cancer
immunotherapy. PLoS ONE 16(12): e0257972. https://doi.org/10.1371/journal.pone.0257972