生物制剂靶向治疗慢性阻塞性肺疾病的研发进展_Chinese Journal of Respiratory and Critical Care Medicine

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刘俊麟 ¹ , 刘祁祁 ² , 李星 ² ,  李竹英 ²

1. ;
2. ;

Corresponding author：

李竹英, Email: lizhuying6808@126.com

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DOI：

10.7507/1671-6205.202410073

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Citation： 刘俊麟, 刘祁祁, 李星, 李竹英. 生物制剂靶向治疗慢性阻塞性肺疾病的研发进展. Chinese Journal of Respiratory and Critical Care Medicine, 2025, 24(8): 601-608. doi: 10.7507/1671-6205.202410073 Copy

1.	Safiri S, Carson-Chahhoud K, Noori M, et al. Burden of chronic obstructive pulmonary disease and its attributable risk factors in 204 countries and territories, 1990-2019: results from the Global Burden of Disease Study 2019. BMJ, 2022, 378: e069679.
2.	Lipson DA, Barnhart F, Brealey N, et al. Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD. N Engl J Med, 2018, 378(18): 1671-1680.
3.	Xiong Y, Hu JQ, Tang HL, et al. Network meta-analysis of the efficacy and safety of monoclonal antibodies and traditional conventional dichotomous agents for chronic obstructive pulmonary disease. Front Med (Lausanne), 2024, 11: 1334442.
4.	Bhatt SP, Rabe KF, Hanania NA, et al. Dupilumab for COPD with Type 2 Inflammation Indicated by Eosinophil Counts. N Engl J Med, 2023, 389(3): 205-214.
5.	Estrada RA, Maselli DJ, Anzueto AR. In COPD with type 2 inflammation despite inhaled triple therapy, dupilumab safely reduced exacerbations. Ann Intern Med, 2023, 176(9): JC102.
6.	Bhatt SP, Rabe KF, Hanania NA, et al. Dupilumab for COPD with Blood Eosinophil Evidence of Type 2 Inflammation. N Engl J Med, 2024, 390(24): 2274-2283.
7.	Lei JT, Martinez-Moczygemba M. Separate endocytic pathways regulate IL-5 receptor internalization and signaling. J Leukoc Biol, 2008, 84(2): 499-509.
8.	Lawrence MG, Teague WG, Feng X, et al. Interleukin-5 receptor alpha (CD125) expression on human blood and lung neutrophils. Ann Allergy Asthma Immunol, 2022, 128(1): 53-60. e3.
9.	Pavord ID, Chapman KR, Bafadhel M, et al. Mepolizumab for Eosinophil-Associated COPD: Analysis of METREX and METREO. Int J Chron Obstruct Pulmon Dis, 2021, 16: 1755-1770.
10.	Pavord ID, Chanez P, Criner GJ, et al. Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease. N Engl J Med, 2017, 377(17): 1613-1629.
11.	Brightling CE, Bleecker ER, Panettieri RA Jr, et al. Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med, 2014, 2(11): 891-901.
12.	George L, Wright A, Mistry V, et al. Sputum Streptococcus pneumoniae is reduced in COPD following treatment with benralizumab. Int J Chron Obstruct Pulmon Dis, 2019, 14: 1177-1185.
13.	Criner GJ, Celli BR, Singh D, et al. Predicting response to benralizumab in chronic obstructive pulmonary disease: analyses of GALATHEA and TERRANOVA studies. Lancet Respir Med, 2020, 8(2): 158-170.
14.	Criner GJ, Celli BR, Brightling CE, et al. Benralizumab for the Prevention of COPD Exacerbations. N Engl J Med, 2019, 381(11): 1023-1034.
15.	Laroche J, Pelletier G, Boulay MÈ, et, al. Anti-IL5/IL5R Treatment in COPD: Should We Target Oral Corticosteroid-Dependent Patients? Int J Chron Obstruct Pulmon Dis, 2023, 18: 755-763.
16.	Zou SP, Yang HY, Ouyang M, et al. Post-marketing safety of anti-IL-5 monoclonal antibodies (mAbs): an analysis of the FDA Adverse Event Reporting System (FAERS). Expert Opin Drug Saf, 2024, 23(3): 353-362.
17.	He F, Yu X, Zhang J, et al. Biomass-related PM2.5 induced inflammatory microenvironment via IL-17F/IL-17RC axis. Environ Pollut, 2024, 342: 123048.
18.	Ma R, Su H, Jiao K, et, al. Association Between IL-17 and Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis. Int J Chron Obstruct Pulmon Dis, 2023, 18: 1681-1690.
19.	Eich A, Urban V, Jutel M, et al. A Randomized, Placebo-Controlled Phase 2 Trial of CNTO 6785 in Chronic Obstructive Pulmonary Disease. COPD, 2017, 14(5): 476-483.
20.	Matera MG, Cazzola M, Page C. Prospects for COPD treatment. Curr Opin Pharmacol, 2021, 56: 74-84.
21.	Yao Y, Zhou J, Diao X, et al. Association between tumor necrosis factor-α and chronic obstructive pulmonary disease: a systematic review and meta-analysis. Ther Adv Respir Dis, 2019, 13: 1753466619866096.
22.	Xia Z, Wang Y, Liu F, et al. Association Between TNF-α-308, +489, -238 Polymorphism, and COPD Susceptibility: An Updated Meta-Analysis and Trial Sequential Analysis. Front Genet, 2022, 12: 772032.
23.	Peñailillo L, Miranda-Fuentes C, Gutiérrez S, et al. Systemic Inflammation but not Oxidative Stress Is Associated with Physical Performance in Moderate Chronic Obstructive Pulmonary Disease. Adv Exp Med Biol, 2024, 1450: 121-130.
24.	Zhang XY, Zhang C, Sun QY, et al. Infliximab protects against pulmonary emphysema in smoking rats. Chin Med J (Engl), 2011, 124(16): 2502-2506.
25.	Rennard SI, Fogarty C, Kelsen S, et al. The safety and efficacy of infliximab in moderate to severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2007, 175(9): 926-934.
26.	Loza MJ, Watt R, Baribaud F, et, al. Systemic inflammatory profile and response to anti-tumor necrosis factor therapy in chronic obstructive pulmonary disease. Respir Res, 2012, 13(1): 12.
27.	Aaron SD, Vandemheen KL, Maltais F, et al. TNFα antagonists for acute exacerbations of COPD: a randomised double-blind controlled trial. Thorax, 2013, 68(2): 142-148.
28.	Xue H, Xie B, Xu N, et al. Etanercept Protected Against Cigarette Smoke Extract-Induced Inflammation and Apoptosis of Human Pulmonary Artery Endothelial Cells via Regulating TNFR1. Int J Chron Obstruct Pulmon Dis, 2021, 16: 1329-1345.
29.	Saco TV, Pepper A, Casale TB. Uses of biologics in allergic diseases: What to choose and when. Ann Allergy Asthma Immunol, 2018, 120(4): 357-366.
30.	Doyle AD, Mukherjee M, LeSuer WE, et, al. Eosinophil-derived IL-13 promotes emphysema. Eur Respir J, 2019 May 30, 53(5): 1801291.
31.	Anzalone G, Albano GD, Montalbano AM, et al. IL-17A-associated IKK-α signaling induced TSLP production in epithelial cells of COPD patients. Exp Mol Med, 2018, 50(10): 1-12.
32.	Yamada H, Hida N, Masuko H, et al. Effects of Lung Function-Related Genes and TSLP on COPD Phenotypes. COPD, 2020, 17(1): 59-64.
33.	Hoy SM. Tezepelumab: First Approval. Drugs, 2022, 82(4): 461-468.
34.	Xia J, Zhao J, Shang J, et al. Increased IL-33 expression in chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol, 2015, 308(7): L619-L627.
35.	Joo H, Park SJ, Min KH, et al. Association between plasma interleukin-33 level and acute exacerbation of chronic obstructive pulmonary disease. BMC Pulm Med, 2021 Mar 15;21(1): 86. Erratum in: BMC Pulm Med, 2021 Oct 29; 21(1): 337.
36.	Faiz A, Mahbub RM, Boedijono FS, et al. IL-33 Expression Is Lower in Current Smokers at both Transcriptomic and Protein Levels. Am J Respir Crit Care Med, 2023, 208(10): 1075-1087.
37.	Rabe KF, Celli BR, Wechsler ME, et al. Safety and efficacy of itepekimab in patients with moderate-to-severe COPD: a genetic association study and randomised, double-blind, phase 2a trial. Lancet Respir Med, 2021, 9(11): 1288-1298.
38.	Yousuf AJ, Mohammed S, Carr L, et al. Astegolimab, an anti-ST2, in chronic obstructive pulmonary disease (COPD-ST2OP): a phase 2a, placebo-controlled trial. Lancet Respir Med, 2022, 10(5): 469-477.
39.	Reid F, Singh D, Albayaty M, et al. A Randomized Phase I Study of the Anti-Interleukin-33 Antibody Tozorakimab in Healthy Adults and Patients With Chronic Obstructive Pulmonary Disease. Clin Pharmacol Ther, 2024, 115(3): 565-575.
40.	Hao W, Li M, Pang Y, et al. Increased chemokines levels in patients with chronic obstructive pulmonary disease: correlation with quantitative computed tomography metrics. Br J Radiol, 2021, 94(1118): 20201030.
41.	Beeh KM, Kornmann O, Buhl R, et al. Neutrophil chemotactic activity of sputum from patients with COPD: role of interleukin 8 and leukotriene B4. Chest, 2003, 123(4): 1240-1247.
42.	Mahler DA, Huang S, Tabrizi M, et al. Efficacy and safety of a monoclonal antibody recognizing interleukin-8 in COPD: a pilot study. Chest, 2004, 126(3): 926-934.
43.	Adage T, Del Bene F, Fiorentini F, et al. PA401, a novel CXCL8-based biologic therapeutic with increased glycosaminoglycan binding, reduces bronchoalveolar lavage neutrophils and systemic inflammatory markers in a murine model of LPS-induced lung inflammation. Cytokine, 2015, 76(2): 433-441.
44.	Nachmias N, Langier S, Brzezinski RY, et al. NLRP3 inflammasome activity is upregulated in an in-vitro model of COPD exacerbation. PLoS One, 2019, 14(5): e0214622.
45.	Chung C, Park SY, Huh JY, et al. Fine particulate matter aggravates smoking induced lung injury via NLRP3/caspase-1 pathway in COPD. J Inflamm (Lond), 2024, 21(1): 13.
46.	Botelho FM, Bauer CM, Finch D, et al. IL-1α/IL-1R1 expression in chronic obstructive pulmonary disease and mechanistic relevance to smoke-induced neutrophilia in mice. PLoS One, 2011, 6(12): e28457.
47.	Pauwels NS, Bracke KR, Dupont LL, et al. Role of IL-1α and the Nlrp3/caspase-1/IL-1β axis in cigarette smoke-induced pulmonary inflammation and COPD. Eur Respir J, 2011, 38(5): 1019-1028.
48.	Calverley PMA, Sethi S, Dawson M, et al. A randomised, placebo-controlled trial of anti-interleukin-1 receptor 1 monoclonal antibody MEDI8968 in chronic obstructive pulmonary disease. Respir Res, 2017 Aug 9;18(1): 153.
49.	Kang MJ, Homer RJ, Gallo A, et al. IL-18 is induced and IL-18 receptor alpha plays a critical role in the pathogenesis of cigarette smoke-induced pulmonary emphysema and inflammation. J Immunol, 2007, 178(3): 1948-1959.
50.	Wang J, Liu X, Xie M, et al. Increased expression of interleukin-18 and its receptor in peripheral blood of patients with chronic obstructive pulmonary disease. COPD, 2012, 9(4): 375-381.
51.	Chen G, Mu Q, Meng ZJ. Cigarette Smoking Contributes to Th1/Th2 Cell Dysfunction via the Cytokine Milieu in Chronic Obstructive Pulmonary Disease. Int J Chron Obstruct Pulmon Dis, 2023, 18: 2027-2038.

1. Safiri S, Carson-Chahhoud K, Noori M, et al. Burden of chronic obstructive pulmonary disease and its attributable risk factors in 204 countries and territories, 1990-2019: results from the Global Burden of Disease Study 2019. BMJ, 2022, 378: e069679.
2. Lipson DA, Barnhart F, Brealey N, et al. Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD. N Engl J Med, 2018, 378(18): 1671-1680.
3. Xiong Y, Hu JQ, Tang HL, et al. Network meta-analysis of the efficacy and safety of monoclonal antibodies and traditional conventional dichotomous agents for chronic obstructive pulmonary disease. Front Med (Lausanne), 2024, 11: 1334442.
4. Bhatt SP, Rabe KF, Hanania NA, et al. Dupilumab for COPD with Type 2 Inflammation Indicated by Eosinophil Counts. N Engl J Med, 2023, 389(3): 205-214.
5. Estrada RA, Maselli DJ, Anzueto AR. In COPD with type 2 inflammation despite inhaled triple therapy, dupilumab safely reduced exacerbations. Ann Intern Med, 2023, 176(9): JC102.
6. Bhatt SP, Rabe KF, Hanania NA, et al. Dupilumab for COPD with Blood Eosinophil Evidence of Type 2 Inflammation. N Engl J Med, 2024, 390(24): 2274-2283.
7. Lei JT, Martinez-Moczygemba M. Separate endocytic pathways regulate IL-5 receptor internalization and signaling. J Leukoc Biol, 2008, 84(2): 499-509.
8. Lawrence MG, Teague WG, Feng X, et al. Interleukin-5 receptor alpha (CD125) expression on human blood and lung neutrophils. Ann Allergy Asthma Immunol, 2022, 128(1): 53-60. e3.
9. Pavord ID, Chapman KR, Bafadhel M, et al. Mepolizumab for Eosinophil-Associated COPD: Analysis of METREX and METREO. Int J Chron Obstruct Pulmon Dis, 2021, 16: 1755-1770.
10. Pavord ID, Chanez P, Criner GJ, et al. Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease. N Engl J Med, 2017, 377(17): 1613-1629.
11. Brightling CE, Bleecker ER, Panettieri RA Jr, et al. Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med, 2014, 2(11): 891-901.
12. George L, Wright A, Mistry V, et al. Sputum Streptococcus pneumoniae is reduced in COPD following treatment with benralizumab. Int J Chron Obstruct Pulmon Dis, 2019, 14: 1177-1185.
13. Criner GJ, Celli BR, Singh D, et al. Predicting response to benralizumab in chronic obstructive pulmonary disease: analyses of GALATHEA and TERRANOVA studies. Lancet Respir Med, 2020, 8(2): 158-170.
14. Criner GJ, Celli BR, Brightling CE, et al. Benralizumab for the Prevention of COPD Exacerbations. N Engl J Med, 2019, 381(11): 1023-1034.
15. Laroche J, Pelletier G, Boulay MÈ, et, al. Anti-IL5/IL5R Treatment in COPD: Should We Target Oral Corticosteroid-Dependent Patients? Int J Chron Obstruct Pulmon Dis, 2023, 18: 755-763.
16. Zou SP, Yang HY, Ouyang M, et al. Post-marketing safety of anti-IL-5 monoclonal antibodies (mAbs): an analysis of the FDA Adverse Event Reporting System (FAERS). Expert Opin Drug Saf, 2024, 23(3): 353-362.
17. He F, Yu X, Zhang J, et al. Biomass-related PM2.5 induced inflammatory microenvironment via IL-17F/IL-17RC axis. Environ Pollut, 2024, 342: 123048.
18. Ma R, Su H, Jiao K, et, al. Association Between IL-17 and Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis. Int J Chron Obstruct Pulmon Dis, 2023, 18: 1681-1690.
19. Eich A, Urban V, Jutel M, et al. A Randomized, Placebo-Controlled Phase 2 Trial of CNTO 6785 in Chronic Obstructive Pulmonary Disease. COPD, 2017, 14(5): 476-483.
20. Matera MG, Cazzola M, Page C. Prospects for COPD treatment. Curr Opin Pharmacol, 2021, 56: 74-84.
21. Yao Y, Zhou J, Diao X, et al. Association between tumor necrosis factor-α and chronic obstructive pulmonary disease: a systematic review and meta-analysis. Ther Adv Respir Dis, 2019, 13: 1753466619866096.
22. Xia Z, Wang Y, Liu F, et al. Association Between TNF-α-308, +489, -238 Polymorphism, and COPD Susceptibility: An Updated Meta-Analysis and Trial Sequential Analysis. Front Genet, 2022, 12: 772032.
23. Peñailillo L, Miranda-Fuentes C, Gutiérrez S, et al. Systemic Inflammation but not Oxidative Stress Is Associated with Physical Performance in Moderate Chronic Obstructive Pulmonary Disease. Adv Exp Med Biol, 2024, 1450: 121-130.
24. Zhang XY, Zhang C, Sun QY, et al. Infliximab protects against pulmonary emphysema in smoking rats. Chin Med J (Engl), 2011, 124(16): 2502-2506.
25. Rennard SI, Fogarty C, Kelsen S, et al. The safety and efficacy of infliximab in moderate to severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2007, 175(9): 926-934.
26. Loza MJ, Watt R, Baribaud F, et, al. Systemic inflammatory profile and response to anti-tumor necrosis factor therapy in chronic obstructive pulmonary disease. Respir Res, 2012, 13(1): 12.
27. Aaron SD, Vandemheen KL, Maltais F, et al. TNFα antagonists for acute exacerbations of COPD: a randomised double-blind controlled trial. Thorax, 2013, 68(2): 142-148.
28. Xue H, Xie B, Xu N, et al. Etanercept Protected Against Cigarette Smoke Extract-Induced Inflammation and Apoptosis of Human Pulmonary Artery Endothelial Cells via Regulating TNFR1. Int J Chron Obstruct Pulmon Dis, 2021, 16: 1329-1345.
29. Saco TV, Pepper A, Casale TB. Uses of biologics in allergic diseases: What to choose and when. Ann Allergy Asthma Immunol, 2018, 120(4): 357-366.
30. Doyle AD, Mukherjee M, LeSuer WE, et, al. Eosinophil-derived IL-13 promotes emphysema. Eur Respir J, 2019 May 30, 53(5): 1801291.
31. Anzalone G, Albano GD, Montalbano AM, et al. IL-17A-associated IKK-α signaling induced TSLP production in epithelial cells of COPD patients. Exp Mol Med, 2018, 50(10): 1-12.
32. Yamada H, Hida N, Masuko H, et al. Effects of Lung Function-Related Genes and TSLP on COPD Phenotypes. COPD, 2020, 17(1): 59-64.
33. Hoy SM. Tezepelumab: First Approval. Drugs, 2022, 82(4): 461-468.
34. Xia J, Zhao J, Shang J, et al. Increased IL-33 expression in chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol, 2015, 308(7): L619-L627.
35. Joo H, Park SJ, Min KH, et al. Association between plasma interleukin-33 level and acute exacerbation of chronic obstructive pulmonary disease. BMC Pulm Med, 2021 Mar 15;21(1): 86. Erratum in: BMC Pulm Med, 2021 Oct 29; 21(1): 337.
36. Faiz A, Mahbub RM, Boedijono FS, et al. IL-33 Expression Is Lower in Current Smokers at both Transcriptomic and Protein Levels. Am J Respir Crit Care Med, 2023, 208(10): 1075-1087.
37. Rabe KF, Celli BR, Wechsler ME, et al. Safety and efficacy of itepekimab in patients with moderate-to-severe COPD: a genetic association study and randomised, double-blind, phase 2a trial. Lancet Respir Med, 2021, 9(11): 1288-1298.
38. Yousuf AJ, Mohammed S, Carr L, et al. Astegolimab, an anti-ST2, in chronic obstructive pulmonary disease (COPD-ST2OP): a phase 2a, placebo-controlled trial. Lancet Respir Med, 2022, 10(5): 469-477.
39. Reid F, Singh D, Albayaty M, et al. A Randomized Phase I Study of the Anti-Interleukin-33 Antibody Tozorakimab in Healthy Adults and Patients With Chronic Obstructive Pulmonary Disease. Clin Pharmacol Ther, 2024, 115(3): 565-575.
40. Hao W, Li M, Pang Y, et al. Increased chemokines levels in patients with chronic obstructive pulmonary disease: correlation with quantitative computed tomography metrics. Br J Radiol, 2021, 94(1118): 20201030.
41. Beeh KM, Kornmann O, Buhl R, et al. Neutrophil chemotactic activity of sputum from patients with COPD: role of interleukin 8 and leukotriene B4. Chest, 2003, 123(4): 1240-1247.
42. Mahler DA, Huang S, Tabrizi M, et al. Efficacy and safety of a monoclonal antibody recognizing interleukin-8 in COPD: a pilot study. Chest, 2004, 126(3): 926-934.
43. Adage T, Del Bene F, Fiorentini F, et al. PA401, a novel CXCL8-based biologic therapeutic with increased glycosaminoglycan binding, reduces bronchoalveolar lavage neutrophils and systemic inflammatory markers in a murine model of LPS-induced lung inflammation. Cytokine, 2015, 76(2): 433-441.
44. Nachmias N, Langier S, Brzezinski RY, et al. NLRP3 inflammasome activity is upregulated in an in-vitro model of COPD exacerbation. PLoS One, 2019, 14(5): e0214622.
45. Chung C, Park SY, Huh JY, et al. Fine particulate matter aggravates smoking induced lung injury via NLRP3/caspase-1 pathway in COPD. J Inflamm (Lond), 2024, 21(1): 13.
46. Botelho FM, Bauer CM, Finch D, et al. IL-1α/IL-1R1 expression in chronic obstructive pulmonary disease and mechanistic relevance to smoke-induced neutrophilia in mice. PLoS One, 2011, 6(12): e28457.
47. Pauwels NS, Bracke KR, Dupont LL, et al. Role of IL-1α and the Nlrp3/caspase-1/IL-1β axis in cigarette smoke-induced pulmonary inflammation and COPD. Eur Respir J, 2011, 38(5): 1019-1028.
48. Calverley PMA, Sethi S, Dawson M, et al. A randomised, placebo-controlled trial of anti-interleukin-1 receptor 1 monoclonal antibody MEDI8968 in chronic obstructive pulmonary disease. Respir Res, 2017 Aug 9;18(1): 153.
49. Kang MJ, Homer RJ, Gallo A, et al. IL-18 is induced and IL-18 receptor alpha plays a critical role in the pathogenesis of cigarette smoke-induced pulmonary emphysema and inflammation. J Immunol, 2007, 178(3): 1948-1959.
50. Wang J, Liu X, Xie M, et al. Increased expression of interleukin-18 and its receptor in peripheral blood of patients with chronic obstructive pulmonary disease. COPD, 2012, 9(4): 375-381.
51. Chen G, Mu Q, Meng ZJ. Cigarette Smoking Contributes to Th1/Th2 Cell Dysfunction via the Cytokine Milieu in Chronic Obstructive Pulmonary Disease. Int J Chron Obstruct Pulmon Dis, 2023, 18: 2027-2038.

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生物制剂靶向治疗慢性阻塞性肺疾病的研发进展

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