有助于研发具有更高特异性和更强亲和力的抗体药物
美国《国家科学院院刊》（PNAS）杂志近日在线发表中科院上海生命科学研究院生物化学与细胞生物学研究所研究员丁建平课题组与第二军医大学教授郭亚军课题组的合作研究成果。该项研究揭示了单克隆抗体药物Efalizumab（商品名Raptiva，Genentech/Xoma）治疗银屑病（牛皮癣）的分子基础。
银屑病是一种常见的皮肤病，以红色或粉红色且带有白色或银色鳞片的增长性皮肤损伤为特征。现有资料表明，白细胞（主要是T细胞）在表皮部分的渗入活动是引起和维持银屑病症状存在的主要驱动力，而在此过程中涉及许多细胞间的黏附分子，其中包括属于整合素（integrin）家族的淋巴细胞功能相关抗原-1（LFA-1）。LFA-1通过其a亚基的I domain与它的最重要的配体——细胞间黏附分子-1（ICAM-1）的domain 1结合，参与介导许多免疫过程。
据介绍，Efalizumab是一种针对LFA-1的a亚基的人源化单克隆抗体药物，可以通过阻止LFA-1与ICAM-1的结合进而抑制白细胞的活动。该抗体药物于2002年通过FDA批准，是目前治疗牛皮癣的最有效的药物之一。丁建平课题组的李胜同学等运用结构生物学和生物化学的方法，研究了Efalizumab的Fab片断和该片断与LFA-1的a亚基的I domain的复合物的晶体结构以及抗原—抗体相互作用的性质。通过对复合物的结构分析以及与文献中生化数据的比较，鉴定了Efalizumab的抗原决定表位（epitope）。
结构分析显示，在复合物结构中I domain处于非激活状态，Efalizumab在I domain上的抗原决定表位不同于ICAM-1的结合位点。进一步通过与已报道的LFA-1 I domain/ICAM-1复合物的结构比较，发现Efalizumab与LFA-1 I domain的结合，会导致Fab的轻链与ICAM-1的domain 2产生空间位置的重叠，从而阻碍了ICAM-1与LFA-1的结合，并进一步抑制了LFA-1的活性。这些结果在分子水平上揭示了Efalizumab对LFA-1的活性产生抑制作用的分子机制，并合理解释了已有的生物化学和免疫学数据。基于该研究结果，研究人员提出了通过对Efalizumab进行定点突变、研发具有更高特异性和更强亲和力的抗体药物的策略，同时依据该抗体药物与小分子药物具有不同作用位点的结果，提出了将Efalizumab与其他小分子药物联合应用以达到更佳治疗效果的方案。这些研究结果对于抗牛皮癣的抗体药物的研发和临床治疗具有重要的指导意义。
该项工作得到科技部、国家自然科学基金委、中国科学院和上海市科委的经费支持。作者: 白开水 时间: 2009-4-2 16:50
有希望就好。作者: 幸运得P 时间: 2009-4-2 18:54
何时才进入临床？几十年不定啊！作者: sznhz 时间: 2009-4-2 19:59
水中月亮！！作者: shubin 时间: 2009-4-2 21:46
恭喜贺喜。希望早日找到病因，[EM52][EM52]作者: 天凉好个秋 时间: 2009-4-3 05:52
[BR]好消息作者: 痴心妄想 时间: 2009-4-3 08:25
鼓掌作者: 几度春秋 时间: 2009-4-3 15:03
遥遥无期作者: KARE 时间: 2009-4-3 17:20
April 2009Questions about your treatment?Information about evaluating your treatment optionsThe National Psoriasis Foundation message boards are buzzing with the recent warning that the biologic drug Raptiva (efalizumab) can cause serious side effects.According to the U.S. Food and Drug Administration (FDA), people who are currently taking or who have discontinued taking Raptiva should be monitored by their health care provider for signs of serious side effects. Anyone who experiences these symptoms should immediately seek medical attention. The FDA warning reminded us how important it is for patients to evaluate their treatment options, especially before starting or stopping any medication. We spoke with dermatologist Stefan Weiss, M.D., clinical instructor at the University of Miami in Florida, about treatment considerations. Finding a treatment that works best for your situation is important, Weiss notes. “Psoriasis is a multi-factorial disease,” he says, meaning that many issues play a role in the disease—and no two people with psoriasis are alike. A treatment that completely clears one patient may have no effect on the next. Weiss stresses the importance of partnering with your dermatologist to learn about the risks and benefits of each drug that you are considering. “No treatment comes without potential sides effects,” Weiss says. Once you’ve determined all of the available options, only then can you determine what the best treatment option is for you. To help you do this, the National Psoriasis Foundation has created a list of helpful questions you should ask when considering a new treatment. [U]译为中文[/U]APRIL 2009你的治疗问题？你的治疗选择资料NPF资讯版传出最近的警告说，生物药物Raptiva (efalizumab)可导致严重的副作用。根据美国食物与药物管理局,（以下称FDA)人们现服用或已停止服用Raptiva,必须监视他们的健康状况是否有严重副作用。有过任何严重病兆者必须即刻寻求医生的诊断。FDA的警告唤醒我们病人对选择治疗的重要，尤其在治疗前或停止医药。与佛罗里达州迈阿密大学皮肤科临床学讲师Stefan Weiss谈过有关治疗上的思考。Weiss 说：找一种药物能最好治疗你的病是重要的。银屑病是多因素造成的。很多论说都充分表现疾病的一面。没有两个银屑病患者是一样的，某种药能使第一患者的银屑消失，但对第二者却无效。Wiess 强调，重要是与医生结为伙伴而讨论而得知你所考虑的药物的利与弊。没有药物不潜在副作用。当你知道所有选择的风险，你才能决定选择你的治疗。这才是你最好的选择。为了帮助你，NPF已作一列表，帮助你当你考虑新的治疗时，什么问题你该问你的医生。作者: KARE 时间: 2009-4-3 17:22
为何不能分段，各位可能看得很迷糊。作者: 水精灵 时间: 2009-4-3 18:01
<div class="msgheader">QUOTE:</div><div class="msgborder"><b>以下是引用<i>KARE</i>在2009-4-3 17:20:00的发言：</b><br/>April 2009Questions about your treatment?Information about evaluating your treatment optionsThe National Psoriasis Foundation message boards are buzzing with the recent warning that the biologic drug Raptiva (efalizumab) can cause serious side effects.According to the U.S. Food and Drug Administration (FDA), people who are currently taking or who have discontinued taking Raptiva should be monitored by their health care provider for signs of serious side effects. Anyone who experiences these symptoms should immediately seek medical attention. The FDA warning reminded us how important it is for patients to evaluate their treatment options, especially before starting or stopping any medication. We spoke with dermatologist Stefan Weiss, M.D., clinical instructor at the University of Miami in Florida, about treatment considerations. Finding a treatment that works best for your situation is important, Weiss notes. “Psoriasis is a multi-factorial disease,” he says, meaning that many issues play a role in the disease—and no two people with psoriasis are alike. A treatment that completely clears one patient may have no effect on the next. Weiss stresses the importance of partnering with your dermatologist to learn about the risks and benefits of each drug that you are considering. “No treatment comes without potential sides effects,” Weiss says. Once you’ve determined all of the available options, only then can you determine what the best treatment option is for you. To help you do this, the National Psoriasis Foundation has created a list of helpful questions you should ask when considering a new treatment. <u>译为中文</u><b>APRIL 2009</b><b>你的治疗问题？你的治疗选择资料</b>NPF资讯版传出最近的警告说，生物药物Raptiva (efalizumab)可导致严重的副作用。根据美国食物与药物管理局,（以下称FDA)人们现服用或已停止服用Raptiva,必须监视他们的健康状况是否有严重副作用。有过任何严重病兆者必须即刻寻求医生的诊断。FDA的警告唤醒我们病人对选择治疗的重要，尤其在治疗前或停止医药。与佛罗里达州迈阿密大学皮肤科临床学讲师Stefan Weiss谈过有关治疗上的思考。Weiss 说：找一种药物能最好治疗你的病是重要的。银屑病是多因素造成的。很多论说都充分表现疾病的一面。没有两个银屑病患者是一样的，某种药能使第一患者的银屑消失，但对第二者却无效。Wiess 强调，重要是与医生结为伙伴而讨论而得知你所考虑的药物的利与弊。没有药物不潜在副作用。当你知道所有选择的风险，你才能决定选择你的治疗。这才是你最好的选择。为了帮助你，NPF已作一列表，帮助你当你考虑新的治疗时，什么问题你该问你的医生。 </div>
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