靶向炎性细胞因子的生物制剂及其临床应用
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摘要
细胞因子可介导许多生物学过程并受到机体的严格调节,其调节的失控可引发一系列疾病如自身免疫炎症和肿瘤。在过去的十几年中,一些能够有效调节细胞因子生物学作用的生物制剂如重组抗炎细胞因子、细胞因子受体以及中和性抗体等被广泛应用到由细胞因子失调引起的相关疾病的治疗。尤其是近年来,一些具有创新性的靶向细胞因子的新型生物制剂在不断涌现。文中对近年来国际上靶向炎症细胞因子(TNF-α、IL-1β、IL-6、IL-17)的生物制剂的研发和临床应用的相关进展进行了综述,指出其副作用和应用风险,并结合其他学者和自己的研究工作提出减少副作用和风险的途径和方法。利用现代生物技术提高抗细胞因子生物制剂针对炎症或肿瘤组织的特异性,是靶向炎性细胞因子生物制剂未来的重要发展方向。
Inflammatory cytokines can mediate many biological processes and are tightly regulated by the body. Loss of control can trigger a range of diseases such as autoimmune inflammation and cancer. Therefore, a number of biological agents that can effectively regulate the biological effects of inflammatory cytokines such as recombinant anti-inflammatory cytokines, cytokine receptors and neutralizing antibodies have been extensively used in the treatment of related diseases caused by the imbalance of inflammatory cytokines. In recent years, in particular, a number of new innovative biological agents for blocking and regulating cytokine activities are emerging. In this article, we review the recent development and clinical use of the biologics targeting TNF-α, IL-1, IL-6 and IL-17, and point out their inherent limitations and clinical risks.Finally, based on the research findings of our own and other scholars, we suggest some approaches and methods for reducing their side-effects and clinical risk. We consider that using modern biotechnology to improve the tissue specificity to inflammatory site and tumor will be an important development direction of such biologics.
Inflammatory cytokines can mediate many biological processes and are tightly regulated by the body. Loss of control can trigger a range of diseases such as autoimmune inflammation and cancer. Therefore, a number of biological agents that can effectively regulate the biological effects of inflammatory cytokines such as recombinant anti-inflammatory cytokines, cytokine receptors and neutralizing antibodies have been extensively used in the treatment of related diseases caused by the imbalance of inflammatory cytokines. In recent years, in particular, a number of new innovative biological agents for blocking and regulating cytokine activities are emerging. In this article, we review the recent development and clinical use of the biologics targeting TNF-α, IL-1, IL-6 and IL-17, and point out their inherent limitations and clinical risks.Finally, based on the research findings of our own and other scholars, we suggest some approaches and methods for reducing their side-effects and clinical risk. We consider that using modern biotechnology to improve the tissue specificity to inflammatory site and tumor will be an important development direction of such biologics.
引文
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[13]Mantovani A.Molecular pathways linking inflammation and cancer.Curr Mol Med,2010,10(4):369-373.
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[17]Bernstein CN,Blanchard JF,Kliewer E,et al.Cancer risk in patients with inflammatory bowel disease:a population-based study.Cancer,2001,91(4):854-862.
[18]Thomas E,Brewster DH,Black RJ,et al.Risk of malignancy among patients with rheumatic conditions.Int J Cancer,2000,88(3):497-502.
[19]Bernatsky S,Renoux C,Suissa S.Demyelinating events in rheumatoid arthritis after drug exposures.Ann Rheum Dis,2010,69(9):1691-1693.
[20]Pugliese D,Guidi L,Ferraro PM,et al.Paradoxical psoriasis in a large cohort of patients with inflammatory bowel disease receiving treatment with anti-TNF alpha:5-year follow-up study.Aliment Pharmacol Ther,2015,42(7):880-888.
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[22]Dallocchio A,Canioni D,Ruemmele F,et al.Occurrence of inflammatory bowel disease during treatment of juvenile idiopathic arthritis with etanercept:a French retrospective study.Rheumatology,2010,49(9):1694-1698.
[23]Arend WP.The balance between IL-1 and IL-1Ra in disease.Cytokine Growth Factor Rev,2002,13(4/5):323-340.
[24]Mertens M,Singh JA.Anakinra for rheumatoid arthritis:a systematic review.J Rheumatol,2009,36(6):1118-1125.
[25]Broderick L,de Nardo D,Franklin BS,et al.The inflammasomes and autoinflammatory syndromes.Annu Rev Pathol:Mech Dis,2015,10:395-424.
[26]Metyas SK,Hoffman HM.Anakinra prevents symptoms of familial cold autoinflammatory syndrome and Raynaud’s disease.J Rheumatol,2006,33(10):2085-2087.
[27]Hawkins PN,Lachmann HJ,Aganna E,et al.Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra.Arthritis Rheum,2004,50(2):607-612.
[28]Goldbach-Mansky R,Dailey NJ,Canna SW,et al.Neonatal-onset multisystem inflammatory disease responsive to interleukin-1βinhibition.N Engl J Med,2006,355(6):581-592.
[29]Stojanovic KS,Delmas Y,Torres PU,et al.Dramatic beneficial effect of interleukin-1 inhibitor treatment in patients with familial Mediterranean fever complicated with amyloidosis and renal failure.Nephrol Dial Transplant,2012,27(5):1898-1901.
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[31]Quartier P,Allantaz F,Cimaz R,et al.A multicentre,randomised,double-blind,placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis(ANAJIS trial).Ann Rheum Dis,2011,70(5):747-754.
[32]Peciuliene S,Burnyte B,Gudaitiene R,et al.Perinatal manifestation of mevalonate kinase deficiency and efficacy of anakinra.Pediatr Rheumatol,2016,14:19.
[33]Grimwood C,Despert V,Jeru I,et al.On-demand treatment with anakinra:a treatment option for selected TRAPS patients.Rheumatology,2015,54(9):1749-1751.
[34]Ottaviani S,MoltóA,Ea HK,et al.Efficacy of anakinra in gouty arthritis:a retrospective study of 40 cases.Arthritis Res Ther,2013,15(5):R123.
[35]Hung AM,Ellis CD,Shintani A,et al.IL-1βreceptor antagonist reduces inflammation in hemodialysis patients.J Am Soc Nephrol,2011,22(3):437-442.
[36]Abbate A,Kontos MC,Grizzard JD,et al.Interleukin-1blockade with anakinra to prevent adverse cardiac remodeling after acute myocardial infarction(Virginia Commonwealth University Anakinra Remodeling Trial[VCU-ART]Pilot study).Am J Cardiol,2010,105(10):1371-1377.e1.
[37]Larsen CM,Faulenbach M,Vaag A,et al.Interleukin-1-receptor antagonist in type 2 diabetes mellitus.N Engl J Med,2007,356(15):1517-1526.
[38]Hoffman HM,Throne ML,Amar NJ,et al.Efficacy and safety of rilonacept(interleukin-1 Trap)in patients with cryopyrin-associated periodic syndromes:results from two sequential placebo-controlled studies.Arthritis Rheum,2008,58(8):2443-2452.
[39]So A,de Smedt T,Revaz S,et al.A pilot study of IL-1inhibition by anakinra in acute gout.Arthritis Res Ther,2007,9(2):R28.
[40]Kuemmerle-Deschner JB,Ramos E,Blank N,et al.Canakinumab(ACZ885,a fully human IgG1 anti-IL-1βmAb)induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome(CAPS).Arthritis Res Ther,2011,13:R34.
[41]Ozdogan H,Ugurlu S.Canakinumab for the treatment of familial Mediterranean fever.Expert Rev Clin Immunol,2017,13(5):393-404.
[42]La Torre F,Caparello MC,Cimaz R.Canakinumab for the treatment of TNF-receptor associated periodic syndrome.Expert Rev Clin Immunol,2017,13(6):513-523.
[43]Ridker PM,Thuren T,Zalewski A,et al.Interleukin-1βinhibition and the prevention of recurrent cardiovascular events:rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study(CANTOS).Am Heart J,2011,162(4):597-605.
[44]Settas LD,Tsimirikas G,Vosvotekas G,et al.Reactivation of pulmonary tuberculosis in a patient with rheumatoid arthritis during treatment with IL-1 receptor antagonists(anakinra).J Clin Rheumatol,2007,13(4):219-220.
[45]Perrin F,Néel A,Graveleau J,et al.Two cases of anakinra-induced neutropenia during auto-inflammatory diseases:drug reintroduction can be successful.La Presse Méd,2014,43(3):319-321.
[46]Turesson C,Riesbeck K.Septicemia with Staphylococcus aureus,beta-hemolytic streptococci group B and G,and Escherichia coli in a patient with rheumatoid arthritis treated with a recombinant human interleukin 1 receptor antagonist(Anakinra).JRheumatol,2004,31(9):1876.
[47]Ruperto N,Brunner HI,Quartier P,et al.Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis.N Engl J Med,2012,367(25):2396-2406.
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