Abstract
Over the past decade, US Food and Drug Administration (FDA)-approved immune checkpoint inhibitors that target programmed death-1 (PD-1) have demonstrated significant clinical benefit particularly in patients with PD-L1 expressing tumors. Toripalimab is a humanized anti-PD-1 antibody, approved by FDA for first-line treatment of nasopharyngeal carcinoma in combination with chemotherapy. In a post hoc analysis of phase 3 studies, toripalimab in combination with chemotherapy improved overall survival irrespective of PD-L1 status in nasopharyngeal carcinoma (JUPITER-02), advanced non-small cell lung cancer (CHOICE-01) and advanced esophageal squamous cell carcinoma (JUPITER-06). On further characterization, we determined that toripalimab is molecularly and functionally differentiated from pembrolizumab, an anti-PD-1 mAb approved previously for treating a wide spectrum of tumors. Toripalimab, which binds the FG loop of PD-1, has 12-fold higher binding affinity to PD-1 than pembrolizumab and promotes significantly more Th1- and myeloid-derived inflammatory cytokine responses in healthy human PBMCs in vitro. In an ex vivo system employing dissociated tumor cells from treatment naïve non-small cell lung cancer patients, toripalimab induced several unique genes in IFN-γ and immune cell pathways, showed different kinetics of activation and significantly enhanced IFN-γ signature. Additionally, binding of toripalimab to PD-1 induced lower levels of SHP1 and SHP2 recruitment, the negative regulators of T cell activation, in Jurkat T cells ectopically expressing PD-1. Taken together, these data demonstrate that toripalimab is a potent anti-PD-1 antibody with high affinity PD-1 binding, strong functional attributes and demonstrated clinical activity that encourage its continued clinical investigation in several types of cancer.
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Introduction
Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have revolutionized cancer treatment in the recent years, affording long-term survival benefit in a broad range of cancer patients. PD-1 is an inhibitory cell surface receptor that is upregulated upon T cell activation. Upon binding to its ligands PD-L1 and PD-L2, that are expressed on antigen presenting cells and/or tumor cells [1], PD-1 recruits the phosphatases SHP1 and SHP2 which in turn suppresses T cell activation and function [2]. While this mechanism of regulating T cell immune response is necessary in maintaining immune tolerance to autoantigens, several tumors over-express PD-L1 in response to inflammatory mediators and downregulate anti-tumor function of T cells leading to tumor immune evasion [64]. Plots were generated with ggplot2 version 3.4 [65], https://cloud.r-project.org/web/packages/ggplot2/index.html) within R-4.0.2 (https://cran.r-project.org). Due to the analysis of DTC samples generated in two groups, batch correction was performed with combat-seq (Zhang et al., NAR Genomics and Bioinformatics, 2020: 2(3):lqaa078) after iterative testing of gene and sample filtering parameters using principal components analysis with the preprocessCore version 1.56 R package (Bolstad B 2023, https://github.com/bmbolstad/preprocessCore).
Pathway analysis
The logFC values from edgeR differential analysis were used for gene set enrichment analysis (GSEA). GSEA was performed with these gene sets via the clusterProfiler R version 4 package (https://bioconductor.org/packages/release/bioc/html/clusterProfiler.html, [66]. The Gene Ontology Biological Process (GOBP) and Hallmark gene sets were obtained from the Broad Institute’s msig.db website (http://www.gsea-msigdb.org/gsea/msigdb). Immune gene sets were extracted from the LM22 matrix [30] by sorting the coefficients for each of the 22 immune cell types and retaining the top 30 genes for each. Immune exhaustion gene sets were derived from the seminal paper on immune exhaustion in the LCMV model system [29].
Statistics
Statistical tests were carried out using GraphPad Prism Software version 9. Statistical tests were used as indicated in the figure legends. p values are reported as follows: *p < 0.05, ** p< 0.01, ***p < 0.001 and ****p < 0.0001.
Data availability
The data supporting the findings in this study are included within the article and its supplementary materials. Raw data that support the findings will be provided upon request.
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Acknowledgements
We thank the patients who volunteered to participate in the toripalimab clinical studies and their families, all the investigators and study site personnel. We thank Marc Pondel, Rosh Dias, Nathalie Vandenkoornhuyse-Yanze and the Coherus Scientific Advisory Board members for thoughtful review and editorial input into the manuscript.
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N. R: Conceptualization, data curation, formal analysis, investigation, writing–original draft, project administration, writing– review and editing. X.W: Investigation, data curation, formal analysis, writing–original draft, writing– review and editing. S. R: Investigation, data curation, formal analysis, writing–original draft, writing– review and editing. D. C: Investigation, Data curation, formal analysis, writing–original draft, writing– review and editing. Sy.T: Investigation, Data curation, formal analysis, writing–original draft, writing– review and editing. S.K: Investigation, Data curation, formal analysis, writing–original draft, writing– review and editing. K.W: Investigation, Data curation, formal analysis, writing–original draft, writing– review and editing. V. K: Investigation, Data curation, formal analysis, writing–original draft, writing– review and editing. V. V: Writing–original draft, writing– review and editing. P. K: Investigation, formal analysis, writing–original draft, writing– review and editing. S.Y: Investigation, formal analysis, writing–original draft, writing– review and editing. T.L: Conceptualization, writing–original draft, project administration, writing– review and editing. S.K: Conceptualization, writing–original draft, project administration, writing– review and editing.
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NR, XW, SR, DC, ST and SK report employment and stock ownership with Coherus Biosciences, Inc. TL reports Coherus Biosciences, Inc. employment and Coherus Biosciences and AstraZeneca stock ownership. PK reports employment with TopAlliance BioSciences Inc. SY reports employment with TopAlliance Biosciences Inc. and Shanghai Junshi Biosciences and stock ownership with Shanghai Junshi Biosciences. VV and SDK report stock ownership with Coherus Biosciences.
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Rajasekaran, N., Wang, X., Ravindranathan, S. et al. Toripalimab, a therapeutic monoclonal anti-PD-1 antibody with high binding affinity to PD-1 and enhanced potency to activate human T cells. Cancer Immunol Immunother 73, 60 (2024). https://doi.org/10.1007/s00262-024-03635-3
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DOI: https://doi.org/10.1007/s00262-024-03635-3