生物制剂-精品医学课件

• Proper name: Adalimumab Tradename: Humira Abbott Laboratories License 0043 12/31/2002
• Adalimumab：纯人抗TNF-a单抗，结构和功能上与天然人 IgG1无法区别，具有很强的TNF-a特异性，一般皮下注射，半 衰期为2周。单用于RA或者和MTX合用。
Tuberculosis and Infliximab-II
In subgroup of 70, 56% extrapulmonary, 79% concurrent immunosuppressives (CS alone or with MTX) Median Rx duration12 wks, 91% of cases occurred low incidence countries-both suggest reactivation Black Box Warning Infliximab-recommend screening and prophylaxis
Choy EHS, Panayi GS. N Engl J Med. 20M01e;d34i4c:a90l7-9A1f6f. airs
Tumor necrosis factor-alpha (TNF) converting enzyme (TACE) was cloned and identified by Immunex Corporation as a new metalloproteinase, an enzyme that uses a bound metal ion to carry out its function.
制剂 重组人IFN-γ (rhuIFN-γ) 重组人IFN-γ (rhuIFN-γ) DAB486IL-2（IL-2融合毒素） cA2（抗TNFα嵌合抗体） B-E8（鼠抗IL-6抗体） IL-1受体阻断剂 可溶性重组IL-1受体(rhu IL-1 R) DBA389IL-2（IL-2融合毒素） Remicade, Etanercept（p75TNFR:Fc融合蛋白）
infliximab (Remicade)
3/4为人源性， 1/4为鼠 源性，抗原结合区 可结合可溶性及细胞膜 上的TNFa，阻断炎症反 应 单独使用或与MTX联用
Medical Affairs
Mechanism of Action Infliximab
Each molecule is able to bind to two molecules of TNF-alpha Forms a relatively stable complex Binds to soluble and membrane bound TNF Such cells lyse in vitro complement mediatedin vivo different mechanism No binding TNF-beta (lymphotoxin alpha).
Serious Adverse Events-
Associated with TNF blockers
Infections Congestive Heart Failure Neurologic Events Malignancies Autoimmunity Hematologic Events Hypersensitivity Others
Approval Date: 2/27/2002
• Infliximab (Remicade )：人IgG1恒定区与具有高度亲和力及中和能力的鼠抗 人TNF-a抗体的Fv段组成的人/鼠嵌合抗体。它不仅能和可溶性TNF-a结合， 也能和跨膜的TNF-a结合。
• Infliximab主要用于和MTX联合治疗对MTX单剂疗效欠佳的患者，从而减轻 RA患者的症状和体征，Infliximab同时具有抑制骨关节破坏的疗效。治疗后的 滑膜标本显示，T-细胞浸润、VCAM-1和E-选择素的表达明显下降，滑膜阻 止合成TNF-a的速度也显著下降。
Those in Yellow will be discussed
Tuberculosis and Infliximab-I
Cases of Tuberculosis have been seen in Infliximab clinical trials. Post-Approval, 295 cases of Infliximab associated tuberculosis reported to FDA (8/02) for an estimated rate of 37cases/100,000 US and 150 cases/100,000 EU compared to background rate tuberculosis RA patients 6.2 cases/100,000 US and 20 cases/100,000 EU
长，每周注射2次
• Etanercept (Enbrel)作为一种可溶性TNFa受体，可中和TNFa的体 内活性，并可和LT结合，主要用于中到重度RA患者，可以减轻患 者的症状和体征，并抑制骨关节结构的破坏。Etanercept可以单独 使用，也可以和MTX联合使用。Etanercept还用于对多种DMARDs 治疗效果不佳，病情中到重度活动的JIA患者。用法为25mg 皮下注 射，每周2次，多数患者应用1-2周后症状即可缓解，少数需用至3 个月才有效。40%的患者可以出现注射局部的皮肤反应，表现为荨
Approved TNF alpha Blocking Agents
Infliximab-(Remicade®)- chimeric (murine variable- human constant) monoclonal antiTNF alpha antibody, FDA approved Oct 1998 Etanercept-(Enbrel®)-fusion protein-2 TNFRII (p75) receptors attached to Fc of human IgG1, FDA approved Nov 1998 Adalimumab-(Humira™)-human monoclonal anti-TNF-alpha antibody, FDA approved Dec 2002
rhu IL-10 MAR（人化抗IL-6受体抗体） Ienercept（p55TNFR:Ig融合蛋白） D2E7（Adalimumab，人抗TNFα抗体）
rhu IL-4 Pegsunercept（PEG-p55TNFR1） CDP870（PEG-Fab连接TNFa受体） IL-1 Trap（I型IL-1受体：Fc融合蛋白） Pralnacasan（Il-1转化酶抑制剂）
ຫໍສະໝຸດ Baidu
生物制剂的种类
1. TNFa和以TNFa为靶向的生物制剂
• Proper name: Etanercept Tradename: Enbrel Immunex Corporation
License 1132 11/02/1998
•
EFcn段tan分e子rce的pDt: N编A码连人接T后N在F-p哺7乳5受动体物可细溶胞部系分表的达D的N融A与合编蛋码白人，I半gG衰1 期
Tuberculosis and Etanercept
No cases of Tuberculosis in etanercept clinical trials. (N=3280 US and EU) 25 cases tuberculosis associated with etanercept reported to FDA MedWatch program as of 2002 52% were extrapulmonary Median etanercept treatment duration 11.5 months Bold Warning in Package Insert
etanercept (Enbrel)
为一可溶性TNFa受体，可中和 TNFa的体内活性 单独使用与MTX疗效相当，副 作用小于MTX 费用为$12,000/年 目前疗效最为肯定的生物制剂
Medical Affairs
Mechanism of Action Etanercept
Binds with TNF alpha and beta Binding is reversible Dissociated TNF remains bioactive
Biological Agents for Autoimmune Disease
定义
• 生物制剂 Biological agents/Biological response modifiers (BMRs)
选择性地以参与免疫反应或炎症过程的分 子或受体为靶目标的单克隆抗体或天然抑 制分子的重组产物
Stable complex with TNF alpha Soluble and membrane bound targeted Lyse cells with membrane bound TNF in vitro in presence of complement No binding of TNF-beta
• Infliximab的推荐剂量是3mg/kg/次，在0、2、6周时使用，剂量要相同，然后 8周1次。这一剂量在部分患者疗效欠佳，可以增至5~6mg/kg/次，头3次注射 后改为每6周一次。用药后约15~20%的患者出现恶心和头疼等不良反应。这 些反应一般是短暂性的，通过减慢注射速度或服用抗组胺药即可得以有效控 制。另有部分患者在用药后12周出现结核感染，因此用药前应注意除外具有 结合感染高危因素的患者，建议要用前摄胸片及PPD(5u)皮试，用药过程中 注意检测感染情况。少数患者在Infliximab治疗后出现ANA和抗dsDNA阳性。
• 对于有慢性感染史和反复感染发作的患者慎用Infliximab和 Etanercept，具有活动性感染的患者禁用。在使用TNF-a抑制 剂的过程中出现新发感染者应密切监测病情，，如出现严重感 染或化脓性感染则需停药。TNF-a抑制剂可能有脱髓鞘副作用， 禁用于多发性硬化患者。
Mechanism of Action Adalimumab
年代 1988 1989 1993 1993 1993 1993 1994 1995 1997 1997 1998 1998 1998 1998 1999 2000 2001 2001
细胞因子 IFN-γ IFN-γ IL-2 TNF IL-6 IL-1 IL-1 IL-2 TNF IL-10 IL-6 TNF TNF IL-4 TNF TNF IL-1 IL-1
麻疹样皮损。反应一般较轻微，具有自限性，不需停药及特殊处理。
仅少数患者需要使用抗组胺药或局部使用糖皮质激素制剂。
Introduction
Members of the Anti-TNF alpha Drug Group have demonstrated efficacy in a number of serious medical conditions including Rheumatoid Arthritis, Juvenile Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Crohn’s Disease They are IMMUNOSUPPRESSIVE
• Proper name: Infliximab
Tradename: Remicade
Manufacturer: Centocor, Inc, Malvern, PA, License #1242
Indication for Use: Improving physical function in patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to methotrexate