依那西普

依那西普
臨床資料
商品名（英语：Drug nomenclature）	恩博（Enbrel）
AHFS/Drugs.com	Monograph
核准狀況	歐 EMA: yes;
懷孕分級	澳: B2 ; ;
给药途径	皮下注射
ATC碼	L04AB01 (WHO) ;
法律規範狀態
法律規範	澳：限医生处方（S4）; 英：处方药（℞-only） (POM); 美：处方药（℞-only）;
藥物動力學數據
生物利用度	58–76% (SC)
药物代谢	单核吞噬细胞系统（推測）
生物半衰期	70–132 hours
识别信息
CAS号	185243-69-0
PubChem SID	10099;
DrugBank	DB00005;
ChemSpider	none;
UNII	OP401G7OJC;
KEGG	D00742;
ChEMBL	ChEMBL1201572;
CompTox Dashboard（英语：CompTox Chemicals Dashboard） (EPA)	DTXSID8040850 ;
ECHA InfoCard	100.224.383
化学信息
化学式	C2224H3475N621O698S36
摩尔质量	51234.9 g/mol

Etanercept（商品名：恩博）是一種治療自體免疫疾病的生物製劑，作用機轉為干擾腫瘤壞死因子（英语：tumor necrosis factor）（TNF，一種可溶性的發炎性細胞激素）的作用，為腫瘤壞死因子抑制劑（英语：TNF inhibitor）。美國食品衛生管理局已許可此藥物用於治療類風濕性關節炎、幼年特發性關節炎、乾癬性關節炎、斑塊狀乾癬和强直性脊柱炎。肿瘤坏死因子-α（TNF-α）是許多器官系統中發炎反應的調節中心，而自體免疫疾病是由過度的免疫反應造成，由於恩博能抑制TNF-α，因此具有治療此類疾病的潛力^[1]。

恩博是一種由重組DNA製造的融合蛋白，將腫瘤壞死因子受體結合到IgG1抗體的恆定端。首先，科學家分別分離人類可溶性腫瘤壞死因子受體2（英语：CD120）（CD120，為TNF-α的受體）的DNA序列，以及人類免疫球蛋白IgG1的Fc（英语：Fragment crystallizable region）區段的DNA序列，然後再把兩者的DNA序列結合，最後就能藉由結合的DNA表現出帶有腫瘤壞死因子受體的IgG1 Fc。1990年代早期布鲁斯·博伊特勒（之後任教於德州大學西南醫學中心（英语：University of Texas Southwestern Medical Center at Dallas））和他的同事首先合成了這種合成蛋白的原型，並發現他在生物體內仍有很好的活性，並能穩定的阻斷TNF的作用^[2]^[3]。

這些研發者也為此合成蛋白申請了專利^[4]，並將所有權利售予生技公司Immunex，該公司其後於2002年被安进（Amgen）併購^[5]。

恩博是一種大型分子，分子量150kDa。它在結合到TNFα後能減少TNFα的作用，減少自體免疫性疾病中過度的發炎反應，例如强直性脊柱炎^[6]、幼年特發性關節炎、乾癬、乾癬性關節炎、類風濕性關節炎和其他可能因TNF-α反應過度而引發的疾病。

醫療用途

美國食品衛生管理局核准恩博用於：

中度到重度類風濕性關節炎（RA，1998年11月）^[7]
中度到重度多關節幼年特發性關節炎（1999年5月）^[8]
乾癬性關節炎（2002年1月）^[9]
强直性脊柱炎（AS，2003年7月）^[10]^[11]
中度到重度乾癬（2004年4月）^[12]

安全性

2008年5月，美國食品藥物管理局由於一些和恩博有關的嚴重感染，而對該藥物發出了黑箱警告（英语：Boxed warning）^[13]。一些報告指出，患者在使用恩博後引發嚴重的感染、敗血症、甚至死亡，當中也包括了潛伏性結核（英语：latent tuberculosis）和乙型肝炎再活化而造成的感染^[14]^[15]。此外，也有在使用恩博後造成糞小桿線蟲過度感染的案例^[16]。

作用機轉

此藥物可減少腫瘤壞死因子（TNF）的作用，因此為一種TNF抑制劑（英语：TNF inhibitor），作為可以結合TNF並使之失去生理作用的游離受體（英语：decoy receptor）^[17]。腫瘤壞死因子α(TNF-α)是一種由淋巴细胞和巨噬细胞這兩種白血球分泌的細胞激素。可藉由吸引更多白血球到發炎處來媒介免疫反應，並藉由其他分子機制啟動和放大發炎反應，抑制此過程對於治療自體免疫性疾病相當重要。 TNF的受體則有兩種：一種附著在白血球細胞表面，與TNF結合後會引發白血球的反應，釋放其他細胞激素；另一種則是「可溶」的受體，在組織液中與TNF結合後會使之失去效用，稱為游離受體。此外，TNF受體分布在幾乎所有有核細胞的表面（紅血球因為沒有核，所以也沒有TNF受體）。而恩博便是模擬游離受體的抑制性作用，但與天然的游離受體不同的是，恩博不是一個單純的TNF受體，而是一種人工合成的融合蛋白，因此在血液中的半衰期大幅增加，能有更顯著且持久的生物效果^[18]。

結構

恩博是由兩種天然的人體蛋白質結合而成的合成蛋白，當中包括了75 kD的可溶性TNF受體和人類免疫球蛋白IgG1的Fc（英语：Fragment crystallizable region）區段^[19]。上述兩種分子經由基因工程結合而形成一個雙體融合蛋白^[19]。恩博是個複雜的分子，結構中包含6個N-多醣基、至多14個O-多醣基和29個雙硫架橋^[20]^[21]^[22]。

相似藥物

可溶性抗腫瘤壞死因子受體
- Pegsunercept（英语：Pegsunercept）
抗腫瘤壞死因子單株抗體
- Infliximab（英语：Infliximab）
- Adalimumab（英语：Adalimumab）
- Certolizumab pegol（英语：Certolizumab pegol）
- Golimumab（英语：Golimumab）

參考資料

^ Feldmann M, Maini RN. Lasker Clinical Medical Research Award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nature Medicine. October 2003, 9 (10): 1245–50. PMID 14520364. doi:10.1038/nm939.
^ Peppel K, Crawford D, Beutler B. A tumor necrosis factor (TNF) receptor-IgG heavy chain chimeric protein as a bivalent antagonist of TNF activity. The Journal of Experimental Medicine. December 1991, 174 (6): 1483–89. PMC 2119031 . PMID 1660525. doi:10.1084/jem.174.6.1483.
^ Peppel K, Poltorak A, Melhado I, Jirik F, Beutler B. Expression of a TNF inhibitor in transgenic mice. Journal of Immunology. November 1993, 151 (10): 5699–703. PMID 7693816. doi:10.1073/pnas.91.1.215.
^ U.S. Patent number: 5,447,851
^ Arthritis Drug Effective for Depression in Psoriasis Sufferers. [2008-01-10]. （原始内容存档于2007-10-20）.
^ Braun J, McHugh N, Singh A, Wajdula JS, Sato R. Improvement in patient-reported outcomes for patients with ankylosing spondylitis treated with etanercept 50 mg once-weekly and 25 mg twice-weekly. Rheumatology. June 2007, 46 (6): 999–1004. PMID 17389658. doi:10.1093/rheumatology/kem069.
^ Siegel, Jay P. Approval of Etanercept for treatment of rheumatoid arthritis (PDF) (Letter). Letter to Sally Gould. Food and Drug Administration. November 2, 1998 [April 14, 2015].
^ Weiss, Karen D. Approval of Etanercept for treatment of polyarticular course juvenile rheumatoid arthritis (JRA) (PDF) (Letter). Letter to Sally Gould. Food and Drug Administration. May 27, 1999 [April 14, 2015].
^ Weiss, Karen D. Approval of Etanercept for treatment of psoriatic arthritis (Letter). Letter to Sally Gould. Food and Drug Administration. January 15, 2002 [April 14, 2015].
^ Keegan, Patricia. Approval of Etanercept for treatment of ankylosing spondylitis (PDF) (Letter). Letter to Douglas Hunt. Food and Drug Administration. July 24, 2003 [April 14, 2015].
^ Maxwell LJ, Zochling J, Boonen A, Singh JA, Veras MM, Tanjong Ghogomu E, Benkhalti Jandu M, Tugwell P, Wells GA. TNF-alpha inhibitors for ankylosing spondylitis. The Cochrane Database of Systematic Reviews. April 2015, 4 (4): CD005468. PMID 25887212. doi:10.1002/14651858.CD005468.pub2.
^ Walton, Marc. Approval of Etanercept for treatment of moderate to severe plaque psoriasis (PDF) (Letter). Letter to Douglas Hunt. Food and Drug Administration. April 30, 2004 [April 14, 2015].
^ Wyeth and Amgen heighten warning of life-threatening infections on skin drug Enbrel. [2008-05-02]. （原始内容存档于2008-05-05）.
^ Safety Update on TNF- α Antagonists: Infliximab and Etanercept (PDF). Food and Drug Administration: 13–14. [2013-12-20].
^ Prescribing Information – Enbrel. [2008-01-10]. （原始内容存档于2007-10-14）.
^ UpToDate.
^ Zalevsky J, Secher T, Ezhevsky SA, Janot L, Steed PM, O'Brien C, Eivazi A, Kung J, Nguyen DH, Doberstein SK, Erard F, Ryffel B, Szymkowski DE. Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection. Journal of Immunology. August 2007, 179 (3): 1872–83. PMID 17641054. doi:10.4049/jimmunol.179.3.1872.
^ Madhusudan S, Muthuramalingam SR, Braybrooke JP, Wilner S, Kaur K, Han C, Hoare S, Balkwill F, Ganesan TS. Study of etanercept, a tumor necrosis factor-alpha inhibitor, in recurrent ovarian cancer. Journal of Clinical Oncology. September 2005, 23 (25): 5950–59. PMID 16135466. doi:10.1200/JCO.2005.04.127.
^ ^19.0 ^19.1 Smola MG, Soyer HP, Scharnagl E. Surgical treatment of dermatofibrosarcoma protuberans. A retrospective study of 20 cases with review of literature. European Journal of Surgical Oncology. October 1991, 17 (5): 447–53. PMID 1936291.
^ Houel S, Hilliard M, Yu YQ, McLoughlin N, Martin SM, Rudd PM, Williams JP, Chen W. N- and O-glycosylation analysis of etanercept using liquid chromatography and quadrupole time-of-flight mass spectrometry equipped with electron-transfer dissociation functionality. Analytical Chemistry. January 2014, 86 (1): 576–84. PMID 24308717. doi:10.1021/ac402726h.
^ Mukai, Yohei; Nakamura, Teruya; Yoshikawa, Mai; Yoshioka, Yasuo; Tsunoda, Shin-ichi; Nakagawa, Shinsaku; Yamagata, Yuriko; Tsutsumi, Yasuo. Solution of the structure of the TNF-TNFR2 complex. Science Signaling. 2010-11-16, 3 (148): ra83. ISSN 1937-9145. PMID 21081755. doi:10.1126/scisignal.2000954.
^ Lamanna, William C.; Mayer, Robert Ernst; Rupprechter, Alfred; Fuchs, Michael; Higel, Fabian; Fritsch, Cornelius; Vogelsang, Cornelia; Seidl, Andreas; Toll, Hansjoerg. The structure-function relationship of disulfide bonds in etanercept. Scientific Reports. 06 21, 2017, 7 (1): 3951. ISSN 2045-2322. PMC 5479810 . PMID 28638112. doi:10.1038/s41598-017-04320-5. 请检查|date=中的日期值 (帮助)

外部連結

安进生技公司的恩博介紹頁面

[titleTNF_defined_as_a_therapeutic_target_for_rheumatoid_arthritis_and_other_autoimmune_diseases_-_Nature_Medicine-1] Feldmann M, Maini RN. Lasker Clinical Medical Research Award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nature Medicine. October 2003, 9 (10): 1245–50. PMID 14520364. doi:10.1038/nm939.

[2] Peppel K, Crawford D, Beutler B. A tumor necrosis factor (TNF) receptor-IgG heavy chain chimeric protein as a bivalent antagonist of TNF activity. The Journal of Experimental Medicine. December 1991, 174 (6): 1483–89. PMC 2119031 . PMID 1660525. doi:10.1084/jem.174.6.1483.

[3] Peppel K, Poltorak A, Melhado I, Jirik F, Beutler B. Expression of a TNF inhibitor in transgenic mice. Journal of Immunology. November 1993, 151 (10): 5699–703. PMID 7693816. doi:10.1073/pnas.91.1.215.

[4] U.S. Patent number: 5,447,851

[title||_DukeMedNews_||_Arthritis_Drug_Effective_for_Depression_in_Psoriasis_Sufferers-5] Arthritis Drug Effective for Depression in Psoriasis Sufferers. [2008-01-10]. （原始内容存档于2007-10-20）.

[pmid17389658-6] Braun J, McHugh N, Singh A, Wajdula JS, Sato R. Improvement in patient-reported outcomes for patients with ankylosing spondylitis treated with etanercept 50 mg once-weekly and 25 mg twice-weekly. Rheumatology. June 2007, 46 (6): 999–1004. PMID 17389658. doi:10.1093/rheumatology/kem069.

[7] Siegel, Jay P. Approval of Etanercept for treatment of rheumatoid arthritis (PDF) (Letter). Letter to Sally Gould. Food and Drug Administration. November 2, 1998 [April 14, 2015].

[8] Weiss, Karen D. Approval of Etanercept for treatment of polyarticular course juvenile rheumatoid arthritis (JRA) (PDF) (Letter). Letter to Sally Gould. Food and Drug Administration. May 27, 1999 [April 14, 2015].

[9] Weiss, Karen D. Approval of Etanercept for treatment of psoriatic arthritis (Letter). Letter to Sally Gould. Food and Drug Administration. January 15, 2002 [April 14, 2015].

[10] Keegan, Patricia. Approval of Etanercept for treatment of ankylosing spondylitis (PDF) (Letter). Letter to Douglas Hunt. Food and Drug Administration. July 24, 2003 [April 14, 2015].

[11] Maxwell LJ, Zochling J, Boonen A, Singh JA, Veras MM, Tanjong Ghogomu E, Benkhalti Jandu M, Tugwell P, Wells GA. TNF-alpha inhibitors for ankylosing spondylitis. The Cochrane Database of Systematic Reviews. April 2015, 4 (4): CD005468. PMID 25887212. doi:10.1002/14651858.CD005468.pub2.

[12] Walton, Marc. Approval of Etanercept for treatment of moderate to severe plaque psoriasis (PDF) (Letter). Letter to Douglas Hunt. Food and Drug Administration. April 30, 2004 [April 14, 2015].

[Wyeth_and_Amgen-13] Wyeth and Amgen heighten warning of life-threatening infections on skin drug Enbrel. [2008-05-02]. （原始内容存档于2008-05-05）.

[FDAReport-14] Safety Update on TNF- α Antagonists: Infliximab and Etanercept (PDF). Food and Drug Administration: 13–14. [2013-12-20].

[titlePrescribing_Information_-_ENBREL-15] Prescribing Information – Enbrel. [2008-01-10]. （原始内容存档于2007-10-14）.

[16] UpToDate.

[17] Zalevsky J, Secher T, Ezhevsky SA, Janot L, Steed PM, O'Brien C, Eivazi A, Kung J, Nguyen DH, Doberstein SK, Erard F, Ryffel B, Szymkowski DE. Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection. Journal of Immunology. August 2007, 179 (3): 1872–83. PMID 17641054. doi:10.4049/jimmunol.179.3.1872.

[pmid16135466-18] Madhusudan S, Muthuramalingam SR, Braybrooke JP, Wilner S, Kaur K, Han C, Hoare S, Balkwill F, Ganesan TS. Study of etanercept, a tumor necrosis factor-alpha inhibitor, in recurrent ovarian cancer. Journal of Clinical Oncology. September 2005, 23 (25): 5950–59. PMID 16135466. doi:10.1200/JCO.2005.04.127.

[pmid1936291-19] 19.0 ^19.1 Smola MG, Soyer HP, Scharnagl E. Surgical treatment of dermatofibrosarcoma protuberans. A retrospective study of 20 cases with review of literature. European Journal of Surgical Oncology. October 1991, 17 (5): 447–53. PMID 1936291.

[20] Houel S, Hilliard M, Yu YQ, McLoughlin N, Martin SM, Rudd PM, Williams JP, Chen W. N- and O-glycosylation analysis of etanercept using liquid chromatography and quadrupole time-of-flight mass spectrometry equipped with electron-transfer dissociation functionality. Analytical Chemistry. January 2014, 86 (1): 576–84. PMID 24308717. doi:10.1021/ac402726h.

[21] Mukai, Yohei; Nakamura, Teruya; Yoshikawa, Mai; Yoshioka, Yasuo; Tsunoda, Shin-ichi; Nakagawa, Shinsaku; Yamagata, Yuriko; Tsutsumi, Yasuo. Solution of the structure of the TNF-TNFR2 complex. Science Signaling. 2010-11-16, 3 (148): ra83. ISSN 1937-9145. PMID 21081755. doi:10.1126/scisignal.2000954.

[22] Lamanna, William C.; Mayer, Robert Ernst; Rupprechter, Alfred; Fuchs, Michael; Higel, Fabian; Fritsch, Cornelius; Vogelsang, Cornelia; Seidl, Andreas; Toll, Hansjoerg. The structure-function relationship of disulfide bonds in etanercept. Scientific Reports. 06 21, 2017, 7 (1): 3951. ISSN 2045-2322. PMC 5479810 . PMID 28638112. doi:10.1038/s41598-017-04320-5. 请检查|date=中的日期值 (帮助)

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