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[资源] 抗体介绍[中英对照]

中文版
抗体
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抗体是免疫系统中的B 淋巴细胞（B细胞）产生的蛋白质。当花粉、细菌等外来物质侵入机体时，抗体能与外来物质上的靶分子（抗原）相结合。靶分子通常是蛋白质，但并不总是蛋白质。抗体也可以与其他细胞表面的抗原相结合，包括肿瘤细胞。抗体与抗原的结合标志着靶细胞或外来物质将被破坏和清除。
抗原与抗体之间的相互作用是非常精确的，可以与钥匙和锁之间关系相比。任意一个特定的B细胞能够产生一种抗体，但是我们身体内有数以百万记的不同B细胞，因此我们身体内有多种多样的抗体。实际上，对于那些我们生活中接触到的数以千计、甚至数以百万记的抗原，我们的机体有能力对每一种抗原发生应答。当一个特定的B细胞遇到一种恰当的抗原时，它能增殖产生大量细胞，其中一些细胞寿命非常长，它们能够在第一次接触抗原之后生存很多年，从而使免疫系统有一定的“记忆力”。与抗原的第二次接触所引起的免疫应答要快得多，也要强得多。这种长期的记忆现象是接种疫苗的基础。其他细胞寿命较短，能产生大量的抗体。
如下图所示，抗体是由四部分蛋白质组成的，两条长链和两条短链，紫色所示为短链。抗体的形状像一个Y字，两边对称，Y形的短臂是与抗原的结合部位，这样一个抗体能与两个靶抗原相结合。

一种抗原能够激活许多种不同的B细胞，产生许多不同的抗体，能与靶分子的不同位置相结合。这些不同抗体的集合叫作多克隆抗体。
在实验室中，可以制造和纯化大量的单种抗体，它们是由同一种B细胞产生的。这些抗体被成为单克隆。利用单克隆抗体进行治疗就是抗体治疗，迄今为止这方面的进展很多。
抗体的抑制肿瘤应用
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我们的免疫系统工作得非常好，有许多不正常的细胞在进展到肿瘤之前就被我们的免疫系统清除了。但不幸的是许多肿瘤细胞起源于正常细胞，所以易于逃避免疫系统的监视。尽管肿瘤细胞的行为与我们体内的外来生物相似，肿瘤细胞不会引起显著的免疫应答。应用免疫系统及其产物来治疗肿瘤很有前途。
可以应用抗体通过多种不同途径来抑制肿瘤的生长:
1. 抗体刺激细胞杀伤作用: 这些抗体能与肿瘤细胞表面的靶蛋白相结合，作为免疫系统破坏该细胞的标记。这个过程被称为抗体依赖的细胞毒作用[antibody dependent cellular cytotoxicity (ADCC)].
2. 受体阻断作用: 抗体可以阻断肿瘤细胞生长信号的接收。
3. 免疫毒素: 这种方法利用抗体携带毒性分子靶向攻击肿瘤细胞。毒性分子可以是能抑制细胞活性的蛋白质，或有放射活性的化合物，能损伤 DNA和诱导凋亡
药物应用
阿来组单抗(Alemtuzumab,Campath) 是一种单克隆抗体，以CD52蛋白为靶向。CD52 蛋白是蛋白质，存在于正常的和肿瘤的B细胞、T细胞和其他免疫细胞上。当抗体与细胞表面相结合之后，抗体的结合可以激活抗体依赖的细胞溶解作用，使细胞破坏。
被用于治疗B细胞慢性淋巴细胞白血病（B-CLL），有一些化疗药物早已用于治疗该病。
静脉输注给药。
不良反应
阿来组单抗可以影响血液中的正常细胞，会导致贫血、增加出血和感染的危险性。因此用药期间应监测细胞计数。
不管男性还是女性，都应该在用药期间采取节育措施，并持续到治疗结束后至少六个月。
有可能发生输液反应。通常在治疗开始后的第一个星期发生，包括发热、寒战、恶心、呕吐和低血压等症状。
其他不良反应包括：皮疹、疲劳、气短、咳嗽、腹泻、头痛、食欲不振、瘙痒、出汗、头晕和腹痛。
贺赛汀
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许多肿瘤存在促进细胞生长和分裂的蛋白质的过度表达。例如，研究发现一些乳腺癌和卵巢癌病例过度表达HER2受体蛋白。更多内容关于HER-2/neu. 对于过度表达HER2受体的肿瘤，贺赛汀?可以用于抑制原发肿瘤和转以肿瘤的生长。
贺赛汀?是一种单克隆抗体，能特异地与HER2蛋白相结合。贺赛汀?抑制敏感肿瘤生长的确切机制尚不清楚，但有证据表明其作用机制不仅一种。有人认为贺赛汀?能通过抑制细胞外生长信号的结合来抑制肿瘤生长，也可以诱导抗体依赖的细胞毒作用（ADCC）。也可能有其他机制。
司徒曼布
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药物使用
司徒曼布 (Herceptin.)可单独使用，也可与其它治疗联合使用。与化疗（chemotherapy）药物的联合使用被证明有更好疗效.
Herceptin可通过手或前臂的静脉作静脉输注。
不良作用：
常见不良作用如下：
• 发热
• 腹泻
• 头痛
• 咳嗽
• 头昏目眩
• 恶心
• 肿瘤部位疼痛
• 皮肤炎症（inflammation）
• 呕吐
• 虚弱无力
这些不良作用通常轻微；随着每次用药，其严重性逐减。
Herceptin对有心脏病、肺部疾病既往史的病人可能会导致比较严重的问题。
当与化疗药物联合使用时，也应考虑化疗药物产生的不良作用。
对Herceptin耐药
对许多病人来说，Herceptin 的有效性会受到耐药的限制，常在用药大约一年后出现。耐药的产生可能是因为有一种不同门生长因子产生，即胰岛素样生长因子（growth factor）- I(IGF-I) 。为了避免这种耐药的产生，研究人员研制出了Herceptin.- DM1。DM1是一种化疗药物，当被附着在Herceptin 上时，抗癌药物对耐药肿瘤的疗效不但可以增加，而且可能比单独使用Herceptin 更为有效。
Gemtuzumab
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药物应用
吉妥单抗［Gemtuzumab ozogamicin (Mylotarg)］是由一种单克隆抗体与一种抗生素连接而成，以CD33 抗原为靶向杀死肿瘤细胞。CD33抗原位于未成熟的白血病细胞和一些正常的幼稚血细胞上，但是不会出现在多能造血干细胞上。当吉妥单抗上的抗体部分与CD33抗原结合以后，药物被细胞吞噬。在细胞内，抗生素被释放出来，造成细胞 DNA断裂而细胞死亡。
吉妥单抗用于治疗复发的急性髓样细胞性白血病，需要满足CD33阳性和年龄大于等于60岁的条件。
吉妥单抗通过静脉输注。
不良反应
吉妥单抗能够影响一些正常血细胞，导致感染。因此在整个用药期间需要监测血细胞计数。
由于该药会对胎儿造成损害，在用药期间需要采取节育措施。
也有可能发生输液反应，一般会在第一次用药的时候和其后的24小时内更容易发生。有严重输液反应的可能，包括肺损伤和低血压。
也有可能发生肝毒性，无论患者既往有无肝病病史。症状包括体重迅速增加、腹痛、肝脏肿大和肝酶指标升高。用药期间需要监测这些反应。
其他不良反应包括：寒战、发热和恶心。
Rituximab
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药物使用
Rituximab (Rituxan. 即Mabthera.) 是一种单克隆抗体（monoclonal antibody），针对CD20 抗原（antigen）。 CD20蛋白（protein）存在于绝大多数成熟的B-细胞，而不存在于骨髓中的B-细胞。这就使得治疗结束后，B-细胞在血液中发生再转移。与抗体结合刺激了被标记了的细胞的破坏。有证据显示，rituximab 可以诱导细胞凋亡（apoptosis）。1997年，rituximab 在美国成为第一个被批准用于癌症治疗的抗体。
Rituximab用于治疗低分化的复发性或难治性（耐药性）的非何杰金氏淋巴瘤（Lymphoma）。
Rituximab通过静脉输液给药，每周一次，通常用药4-8次。
不良作用
• 发恐
• 畏寒
• 感染
• 淋巴细胞（lymphocyte）计数下降
输液反应可能发生。在第一次输液时，许多病人有发热、畏寒的反应。可用其它药物处理或减慢输液速度成停止输液。其它更严重的输液反应也可能发生。
某些病人还可能出现肺部的不良反应，如咳嗽、鼻炎。有些病人还可出现更严重的不良反应。
Ibritumomab
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药物应用
Ibritumomab tiuxetan (Zevalin)是一种抗CD20的单克隆抗体。CD20蛋白位于大多数成熟的B细胞上，无论是正常的还是肿瘤性的，但CD20不存在于骨髓的B细胞上。Zevalin是放射免疫治疗的典型的例子，即采用抗体携带放射活性物质。Zevalin携带的是两种不同的同位素，有放射活性的抗体复合物直接进入目标肿瘤细胞，放射能量杀死靶细胞并波及周围的其他肿瘤细胞和一些正常细胞。
整个Zevalin治疗方案需要7～9天。第一天给予输注 rituximab (Rituxan)，用量较单独应用时小。4小时内再给予Zevalin的第一次给药，这次给药包括放射性同位素铟－111。这种同位素能在特殊的显像检测中显像。在第六天前要进行2～3次显像以明确由放射活性的抗体位于哪里，以保证安全。如果这些抗体的分布正常，则第7天至第9天给予低剂量的rituximab输注，再在4小时内第二次给予Zevalin输注。这次给予的Zevalin所携带的放射活性同位素与第一次不同，为钇-90，它能够杀死靶细胞。
这种治疗方案中所用的rituximab的剂量小于单独应用rituximab治疗时，并能够通过Zevalin抗体与靶细胞相结合的形式来提高特异性。
Zevalin用于治疗一定类型的非霍奇金淋巴瘤，内包括那些rituximab单用治疗无效的。
特别注意事项
铟-111标记的抗体的放射性非常低，因此注射后无特殊注意事项。
但是，如果不注意下列事项的话，钇-90标记的抗体能使患者周围其他人暴露于放射线，因此在给药后1周的治疗期间：
不良反应
常见不良反应包括：
• 恶心和呕吐
• 腹痛
• 腹泻
• 咳嗽
• 气短h
• 头晕
• 食欲不振
• 关节疼痛
• 神经过敏
• 淤斑
大多数病例出现血细胞计数下降，有可能影响机体抗感染的能力、抑制凝血、引起乏力和疲劳。监测血细胞计数和避免其他影响凝血的药物治疗非常重要。
尽管应用Zevalin?治疗所用的剂量较单独应用时小，仍有可能发生与rituximab相关的不良反应。
Tositumomab
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药物应用
Tositumomab (Bexxar®

是一种抗CD20 单克隆抗体，它与其它单克隆抗体的不同在于，抗体与一种放射性碘（I131）相结合。利用抗体将放射活性碘带至肿瘤细胞，从而利用放射性杀死肿瘤细胞，这种治疗方法叫做放射免疫治疗。
Tositumomab用于治疗复发或难治性（耐药）非霍奇金淋巴瘤。
Tositumomab分为两套输注剂，一套无放射活性的抗体和一套由放射活性的抗体。
不良反应
tositumomab治疗常见的不良反应为细胞计数降低。
其他常见不良反应包括：
• 虚弱
• 发热
• 恶心
• 感染
• 咳嗽
输液过敏反应也可能发生。曾经接触过鼠类蛋白、发生抗鼠类免疫反应的病人，发生这类反应的危险性更高。
一些病人会发生甲状腺功能低下，因此在Tositumomab治疗期间应当应用甲状腺阻断剂，并在治疗后每年筛查甲状腺功能低下。
由于这种治疗中，放射活性物质会在机体内存在一定时间，病人应当遵循特殊规则和注意事项，以免对其他人造成损害。

英文版
Introduction to Antibodies
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Antibodies are proteins produced by B-lymphocytes (B-cells), cells of the immune system. In the body, antibodies bind to target molecules (antigens) present on foreign objects that enter the body, such as pollen or bacteria. The target molecules are often but not always proteins. Antibodies may also bind to antigens located on the surface of other cells, including cancer cells. The binding of an antibody to an antigen marks the target cell or foreign object for destruction and removal.
The interaction between antibody and antigen is very precise and is analogous to the interaction between a lock and key. Any given B-cell can produce only one type of antibody but our cells contain millions of different B-cells. Because of this, there are many different kinds of antibodies in our bodies. In fact, our bodies have the ability to respond to ech of the many thousands or even millions of different possible antigens to which we may be exposed during our lifetime. When a particular B-cell encounters the appropriate antigen it reproduces to create a large number of cells. Some of the resulting cells are very long-lived. They can live for years after the initial 'challenge' with antigen and provide the immune system with a form of memory. A second exposure to the same antigen leads to to a much more rapid and virogorous response. This long term memory is the basis of vaccinations. The rest of the cells are short-lived cells that produce large amounts of antibodies.
As shown below, antibodies are composed of four proteins, two larger chains and two smaller chains, which are represented in purple. They are shaped like Ys and each side is identical so that an antibody is able to bind to two copies of its target, one per each short arm of the Y.

Any given antigen can lead to the activation of many different B-cells and the production of many different antibodies, all directed against different portions of the same target. A mixture of different antibodies is said to be polyclonal.
In the laboratory, it is possible to produce and purify large amounts of a single type of antibody, produced by a single type of B-cell. These antibodies are said to be monoclonal. The antibody based treatments developed so far utilize monoclonal antibodies.
Antibodies in Cancer Treatment
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Our immune system performs its job remarkably well. It is possible that many abnormal cells are eliminated by the immune system before they can progress to cancer. Unfortunately many cancer cells tend to go unnoticed by the immune system because they originate from normal body cells. Despite the fact that they behave like foreign organisms within our bodies, cancer cells often do not elicit a significant immune response. The use of the immune system and its products in the treatment of cancer has yielded promising results.
Antibodies can be used to inhibit the growth of cancer cells in several different ways:
1.       Antibodies that stimulate cell killing: These antibodies function by targeting proteins on the surface of cancer cells. The antibodies themselves mark the cell for destruction by cells of the immune system. This process is termed antibody dependent cellular cytotoxicity (ADCC).
2.       Blockage of receptors: These antibodies may function as a blockade to the receipt of required growth signals.
3.       Immunotoxins: This approach utilizes antibodies to target toxic molecules to the cancer cells. These toxic molecules can be proteins that inhibit cellular activities or radioactive compounds that cause DNA damage and the induction of apoptosis.
The first two mechanisms of action are depicted in the diagram below:
In the top image, antibodies (purple) bound to a cancer cell (blue) are recognized by killer T-cells (aqua) via specific antibody receptors (yellow) on the surface of the T-cells. These cells then produce toxic compounds that kill the cancer cell.
In the second mechanism, the bound antibodies block the attachment of growth factors (green) to the cancer cell, depriving it of required pro-growth signals.
The third mechanism is shown below. Antibodies carrying a toxic substance target the drug to cancer cells leading to the internalization of the poison and the death of the cancer cells.
Drug Usage
Alemtuzumab (Campath® is a monoclonal antibody directed against the CD52 protein. The CD52 protein is present normal and cancerous B and T cells and other immune cells. It is thought that after the antibody binds to the surface of the cells that binding of the antibody stimulates the destruction of the tagged cells, through antibody-dependent lysis.
Alemtuzumab is used in the treatment B-cell chronic lymphocytic leukemia (B-CLL) that have already been treated with certain chemotherapy drugs.
Alemtuzumab is administered as an IV infusion.
Adverse Effects
Alemtuzumab can affect normal cells of the blood, which can result in anemia, increased risk of bleeding, and infection. For this reason blood counts will be monitored throughout the duration of treatment.
Birth control should be used during treatment and at least six months after treatment has ended both men and women.
Infusion reactions may also occur. These reactions are much more likely to occur during the first week of treatment. Symptoms may include fever, chills, nausea, vomiting, and low blood pressure.
Other side effects may include: rash, fatigue, shortness of breath, coughing, diarrhea, headache, loss of appetite, itching, sweating, dizziness, and abdominal pain.
Introduction to Herceptin.
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Many tumors overproduce proteins necessary for cell growth and division. An example is the overexpression of the HER2 receptor protein, which is found in excessive quantities in some breast and ovarian cancer cases. More information on HER-2/neu. In cancers that do overexpress this receptor, Herceptin® may help to prevent the growth of primary and metastatic tumors.
Herceptin® is a monoclonal antibody specifically engineered to bind to the HER2 protein. It is not known exactly how Herceptin® functions to stop the growth of sensitive tumors, but there is evidence that it may have more than one mechanism of action.  It is thought that Herceptin® may prevent tumor growth by inhibiting the binding of extracellular growth signals to receptors on the cell surface. The normal signaling process and activity of Herceptin® are shown in the animation below.
Herceptin® may also be able to induce antibody dependent cellular cytotoxicity (ADCC). Other mechanisms are also possible.
Trastuzumab
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Drug Usage
Trastuzumab (Herceptin® is given both as a solo treatment and in conjunction with other treatments. Combination treatment with chemotherapy has been found to yield better results.
Herceptin® is given via intravenous infusion in the arm or hand.
Adverse Effects:
Common side effects include:
•       Fever
•       Diarrhea
•       Headache
•       Cough
•       Lightheadedness
•       Nausea
•       Pain at the tumor site
•       Skin inflammation
•       Vomiting
•       Weakness
These side effects are usually mild and decrease in severity sith each administration of the drug.
Herceptin® can cause more serious problems in patients with other pre-existing conditions, such as heart and lung disorders.
When taken in conjunction with chemotherapy the side effects of those drugs must also be taken into consideration.
Resistance to Herceptin®
For many patients, the efficacy of Herceptin® is limited by the development of resistance, often after about one year of treatment. It is thought that the production of a different growth factor,insulin-like growth factor-I (IGF-I), may be responsible for this resistance. In an effort to bypass resistance researchers have created Herceptin-DM1®. DM1 is a chemotherapy drug that when attached to Herceptin® not only has anti-tumor effects on resistant cancers but perhaps may also be more effective than Herceptin® alone.
Gemtuzumab
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Drug Usage
Gemtuzumab ozogamicin (Mylotarg® is a monoclonal antibody directed against the CD33 antigen that is attached to an antibiotic that kills tumor cells. The CD33 antigen is present on immature leukemic cells and on some normal early-stage blood cells, however, it is not found on pluripotent hematopoietic stem cells. After the antibody portion of this drug binds to the CD33 antigen it is taken into the cell. Inside the cell, the antibiotic is released and causes breaks in cellular DNA that result in cell death.
Gemtuzumab is used in the treatment relapsed acute myeloid leukemia (AML) that tests positive for CD33 in patients 60 years or older.
Gemtuzumab is administered as an IV infusion.
Adverse Effects
Gemtuzumab can affect certain normal cells of the blood, which can result in infection. For this reason blood counts will be monitored throughout the duration of treatment.
Birth control should be used during treatment as this drug may cause harm to the unborn child.
Infusion reactions may also occur. These reactions are much more likely to occur during the first infusion and the 24-hour period that follows. Reactions may be severe and include pulmonary effects and low blood pressure.
Hepatotoxicity may also occur in patients with and without a history of liver problems. Symptoms include rapid weight gain, abdominal pain, enlarged liver and elevated liver enzymes. Patients should be monitored closely for these effects.
Other side effects may include: chills, fever, and nausea.
Rituximab
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Drug Usage
Rituximab (Rituxan® or Mabthera® is a monoclonal antibody directed against the CD20 antigen. The CD20 protein is present on the majority of mature B-cells but not on B-cells in the bone marrow. This allows the repopulation of the blood with B-cells after treatment ends. Binding of the antibody stimulates the destruction of the tagged cells. Evidence also suggests that rituximab may induce apoptosis in cells. In 1997, rituximab became the first antibody approved for the treatment of cancer in the United States.
Rituximab is used in the treatment of low-grade relapsed or refractory (treatment resistant) Non-Hodgkin's Lymphoma.
Rituximab is administered as an IV infusion once a week usually for 4 to 8 doses.
Adverse Effects
•       Fever
•       Chills
•       Infection
•       Lowered lymphocyte count
Infusion reactions may also occur. During the first infusion many patients experience such a reaction with fever and chills. These symptoms can be treated with other medications or by slowing or stopping the infusion. Other, more severe reactions may also occur.
Some patients may also experience pulmonary side effects that include cough and rhinitis. Other patients may experience more severe side effects.
Ibritumomab
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Drug Usage
Ibritumomab tiuxetan (Zevalin® is a monoclonal antibody directed against the CD20 antigen. The CD20 protein is present on the majority of mature B-cells, normal and cancerous, but not on B-cells in the bone marrow. However, Zevalin® is an example of radioimmunotherapy in that the antibody is attached to a radioactive element, one of two different isotopes in the case of Zevalin®. The radioactive portion of the antibody complex is directly delivered to target cancer cells and the energy released from radiation kills the target cell and spreads to other nearby cancer cells and some normal cells.
Zevalin® is given as a part of a regimen that takes 7 to 9 days to complete. On day 1 an infusion of rituximab (Rituxan® is given at a lower dose than if this treatment were used alone. Within 4 hours of this infusion the first dose of Zevalin® is given. This dosage includes the Indium-111 radioactive isotope. This isotope is able to be seen by using a special imaging test. These imaging tests are performed 2 to 3 times by day 6 and provide safety information about where in the body the radioactive antibodies are found. If the distribution of these antibodies is normal then on day 7 to day 9 a second, lower-dose infusion of rituximab is given and within 4 hours of this infusion a second infusion of Zevalin® is given. This dose of Zevalin® include a different radioactive isotope, Yttrium-90, that is capable of killing targeted cells.
The rituximab infusion used in this regimen is lower than that used if treating with rituximab alone and serves to increase the specificity by which the Zevalin® antibody binds to target cells.
Zevalin® is used to treat certain types of non-Hodgkin's lymphoma, including those that are unresponsive to rituximab alone.
Special Precautions
The Indium-111-fused antibody supplies very small amounts of radiation, therefore no special precautions are necessary after this infusion.
However, the Yttrium-90-fused antibody could result in other people being exposed to radiation if these precautions are not followed until 1 week after treatment is finished:
Adverse Effects
Common side effects include:
•       Nausea and vomiting
•       Abdominal pain
•       Diarrhea
•       Cough
•       Shortness of breath
•       Dizziness
•       Loss of appetite
•       Joint pain
•       Nervousness
•       Bruising
Blood cell counts become low in most cases, which may alter the body's ability to fight infections, decrease blood clotting, and cause weakness and fatigue. It is important that these counts be monitored and that no other medications that alter blood clotting be taken.
Though the dosage of rituximab is lower in the Zevalin® than when given alone there is still a chance of experiencing adverse effects associated with this drug. More information about rituximab.

[ Last edited by johnsooh on 2007-6-11 at 22:19 ]

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