Abstract
Aim: To compare the protein–protein interactions of antibodies targeting PD-1 and its ligand (PD-L1) with their targets in an attempt to explain the antibodies' binding affinity. Materials & methods: The structural features of complexes between pembrolizumab, nivolumab, durvalumab, atezolizumab, avelumab and PD-1/PD-L1 are described, with the use of software and based on crystallographic data. Results: Pembrolizumab has more structural features, including the number and type of the bonds and total binding surface area, which could rationalize its different clinical behavior compared with nivolumab. Similarly, protein–protein interactions with PD-L1 differ among durvalumab, atezolizumab and avelumab. Conclusion: Differential protein–protein interactions between antibodies and PD-1/PD-L1 may indicate differential clinical activity; however, further research is needed to provide evidence.
Plain language summary
This study looked at different immunotherapy drugs used to treat cancer. These drugs bind to two different proteins, called PD-1 and PD-L1, that are part of our immune system. These proteins usually act as brakes in our immune system. The drugs block the brakes, which boosts the immune system and improves the immune defense against cancer. Using computer images, the authors compared how each drug binds to PD-1/PD-L1. The results showed that these drugs bind to PD-1 and PD-L1 with different chemical bonds. These bonds can be smaller or larger depending on the drug. The drugs' different chemical bonds with PD-1/PD-L1 might show that they do not act exactly the same when they are given to patients. However, further studies are needed for more information.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 11(11), 3887–3895 (1992).
- 2. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 8(5), 765–772 (1996).
- 3. . The PD-1 pathway in tolerance and autoimmunity. Immunol. Rev. 236, 219–242 (2010). • A comprehensive review on the role of PD-1 in immune tolerance.
- 4. The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J. Immunol. 181(10), 6738–6746 (2008).
- 5. . PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26, 677–704 (2008).
- 6. . PD-L2 expression extends beyond dendritic cells/macrophages to B1 cells enriched for V(H)11/V(H)12 and phosphatidylcholine binding. Eur. J. Immunol. 37(9), 2405–2410 (2007).
- 7. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep. 19(6), 1189–1201 (2017).
- 8. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 545(7655), 495–499 (2017).
- 9. . Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl Acad. Sci. USA 99(19), 12293–12297 (2002). •• A pivotal study suggesting that the blockade of the PD-1/PD-L1 axis may provide a promising strategy for specific tumor immunotherapy.
- 10. . Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J. Immunother. Cancer 6(1), 8 (2018).
- 11. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375(19), 1823–1833 (2016). • A pivotal phase III trial proving the efficacy of pembrolizumab in PD-L1-positive non-small-cell lung cancer.
- 12. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 393(10183), 1819–1830 (2019).
- 13. Nivolumab monotherapy for first-line treatment of advanced non-small-cell lung cancer. J. Clin. Oncol. 34(25), 2980–2987 (2016).
- 14. Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC. N. Engl. J. Med. 383(14), 1328–1339 (2020).
- 15. Durvalumab with or without tremelimumab vs standard chemotherapy in first-line treatment of metastatic non-small cell lung cancer: the MYSTIC phase 3 randomized clinical trial. JAMA Oncol. 6(5), 661–674 (2020).
- 16. PD-L1 immunohistochemistry assays for lung cancer: results from phase 1 of the blueprint PD-L1 IHC assay comparison project. J. Thorac. Oncol. 12(2), 208–222 (2017). • A study investigating the analytical and clinical comparability of different PD-L1 assays.
- 17. . A medicinal chemist's guide to molecular interactions. J. Med. Chem. 53(14), 5061–5084 (2010).
- 18. Intriguing role of water in protein–ligand binding studied by neutron crystallography on trypsin complexes. Nature Communications 9(1), 3559 (2018).
- 19. . Immunotherapy in the first-line setting in wild-type NSCLC. Curr. Oncol. 28(6), 4457–4470 (2021).
- 20. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N. Engl. J. Med. 376(25), 2415–2426 (2017).
- 21. First-line nivolumab plus ipilimumab in advanced NSCLC: 4-year outcomes from the randomized, open-label, phase 3 CheckMate 227 part 1 trial. J. Thorac. Oncol. 17(2), 289–308 (2022).
- 22. Comparison of programmed death-ligand 1 protein expression between primary and metastatic lesions in patients with lung cancer. J. Immunother. Cancer 9(4), e002230 (2021).
- 23. Feasibility and safety of PD-1/L1 inhibitors for non-small cell lung cancer in front-line treatment: a Bayesian network meta-analysis. Transl. Lung Cancer Res. 9(2), 188–203 (2020).
- 24. . Immune checkpoint inhibitors, alone or in combination with chemotherapy, as first-line treatment for advanced non-small cell lung cancer. A systematic review and network meta-analysis. Lung Cancer 134, 127–140 (2019).
- 25. . Network meta-analysis comparing efficacy, safety and tolerability of anti-PD-1/PD-L1 antibodies in solid cancers. J. Cancer 12(14), 4372–4378 (2021).
- 26. Comparison of the inhibition mechanisms of adalimumab and infliximab in treating tumor necrosis factor α-associated diseases from a molecular view. J. Biol. Chem. 288(38), 27059–27067 (2013).
- 27. . PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations. Hum. Vaccin. Immunother. 15(5), 1111–1122 (2019).
- 28. . Progress in PD-1/PD-L1 pathway inhibitors: from biomacromolecules to small molecules. Eur. J. Med. Chem. 186, 111876 (2020).
