免疫6

Monoclonal Antibodies Are Effective in Treating Some TumorsMonoclonal antibodies have been used in various ways as experimental immunotherapeutic agents for cancer. For example,anti-idiotype monoclonal antibodies have been used with some success in treating human B-cell lymphomas and T-cell leukemias. In one remarkable study, R. Levy and his colleagues successfully treated a 64-year-old man with terminal B-cell lymphoma. At the time of treatment, the lymphoma had metastasized to the liver, spleen, bone marrow,and peripheral blood. Because this was a B-cell cancer, the membrane-bound antibody on all the cancerous cells had the same idiotype.By the procedure outlined in Figure 22-14,these researchers produced mouse monoclonal antibody specific for the B-lymphoma idiotype.When this mouse monoclonal anti-idiotype antibody was injected into the patient, it bound specifically to the B-lymphoma cells, because these cells expressed that particular idiotype. Since B-lymphoma cells are susceptible to complement-mediated lysis, the monoclonal antibody activated the complement system and lysed the lymphoma cells without harming other cells. After four injections with this anti-idiotype monoclonal antibody, the tumors began to shrink, and this patient entered an unusually long period of complete remission.However, this approach requires that a custom monoclonal antibody be raised for each lymphoma patient. This is prohibitively expensive and cannot be used as a general therapeutic approach for the thousands of patients diagnosed each year w ith B 单克隆抗体可有效治疗某些肿瘤单克隆抗体已被用于以各种方式为实验免疫治疗剂用于癌症。

例如，抗独特型的单克隆抗体已被用于在治疗人B细胞淋巴瘤和T细胞白血病的一些成功。

在一个显着的研究中，利维河和他的同事们成功治疗64岁的男子与终端B细胞淋巴瘤。

在治疗时，淋巴瘤已经转移到肝脏，脾脏，骨髓，末梢血。

因为这是一个B细胞癌，在所有癌细胞的膜- 结合的抗体具有相同的独特型。

由图22-14所概述的程序，这些研究人员产生特异于B-淋巴瘤独特型小鼠单克隆抗体。

当该小鼠单克隆抗独特型抗体注射入病人，它特异性结合的B淋巴瘤细胞，因为这些细胞表达特定的独特型。

由于B-淋巴瘤细胞易受补体介导的裂解，单克隆抗体激活补体系统和裂解淋巴瘤细胞而不伤害其他细胞。

经过四次注射用这种抗独特型单克隆抗体，肿瘤开始缩小，这病人进入完全缓解的一个特别长的时间。

lymphoma.Recently, Levy and his colleagues have used direct immunization to recruit the immune systems of patients to an attack against their B lymphoma. In a clinical trial with 41 B-cell lymphoma patients, the genes encoding the rearranged immunoglobulin genes of the lymphomas of each patient were isolated and used to encode the synthesis of recombinant immunoglobulin that bore the idiotype typical of the patient’s tumor. Each of these Igs was coupled to keyhole limpet hemocyanin (KLH), a mollusk protein that is often used as a carrier protein because of its efficient recruitment of T-cell help. The patients were immunized with their own tumor-specific antigens, the idiotypically unique immunoglobulins produced by their own lymphomas. About 50% of the patients developed anti-idiotype antibodies against their tumors. Significantly, improved clinical outcomes were seen in the 20 patients with anti-idiotype responses, but not in the others. In fact, 2 of these 20 experienced complete remission.Despite its promise, the anti-idiotypic approach is by its very nature patient-specific.A more general monoclonalantibody therapy for B-cell lymphoma is based on the fact that mostB cells, whether normal or cancerous, bear lineagedistinctive antigens. One such determinant, CD20, has been the target of intensive efforts; a monoclonal antibody to it,raised in mice and engineered to contain mostly human sequences,has been useful in the treatment of B-cell lymphoma (see Clinical Focus, Chapter 5). Aside from CD20, a number of tumor-associated antigens (Table 22-4) are being tested in clinical trials for their suitability as targets for antibody-mediated然而，这种方法要求单克隆抗体对每个淋巴瘤患者定制。

这是昂贵的，不能用作对成千上万的患者每年诊断患有B细胞淋巴瘤的一般的治疗方法。

近日，Levy和他的同事们用直接免疫招募患者的免疫系统来对抗他们的B细胞淋巴瘤的攻击。

在临床试验中有41个B细胞淋巴瘤的患者，编码每个患者的淋巴瘤的重排的免疫球蛋白基因的基因分离并用于重组免疫球蛋白的合成该孔的独特型典型患者的肿瘤进行编码。

每个这些Igs的被耦合到匙孔血蓝蛋白（KLH），即常使用，因为T细胞的帮助下其高效招募作为载体蛋白质的软体动物蛋白质。

的患者进行免疫自身肿瘤特异性抗原，由自己淋巴瘤产生的idiotypically独特的免疫球蛋白。

约50％的患者出现抗独特型抗体对他们的肿瘤。

显著改善临床结果被视为在20例抗独特型反应，但不是在其他。

事实上，这些2 20经历完全缓解。

尽管它的诺言，抗独特型的方法是通过其本质患者特异性。

更一般的单克隆抗体治疗B细胞淋巴瘤是基于这样的事实：大多数B细胞，是否正常或癌，熊谱系独特抗原。

这样的一个决定因素，CD20，一直积极努力的目标;单克隆抗体是，提出了在小鼠和设计包含人类大多序列，已在B细胞淋巴瘤的治疗有用（见临床重点，第5章）。

除了CD20，一些肿瘤相关抗原（表22-4）正在临床试验中对他们的适合作为目标抗体介导的抗肿瘤治疗试验。

anti-tumor therapy.A variety of tumors express significantly increased levels of growth-factor receptors, which are promising targets for anti-tumor monoclonal antibodies. For example, in 25 to 30 percent of women with metastatic breast cancer, a genetic alteration of the tumor cells results in the increased expression of HER2, an epidermal-growth-factor–like receptor. An anti-HER2 monoclonal antibody was raised in mice and the genes encoding it were isolated. Except for the sequences encoding the antibody’s CDRs, the mouse Ig sequences were replaced with human Ig counterparts. This prevents the generation of human anti-mouse antibodies (HAMAs) and allows the patient to receive repeated doses of the “humanized” anti-HER2 in large amounts (100 milligrams or more).Preparations of this antibody, called Herceptin, are now commercially available for the treatment of HER2-receptor–bearing breast cancers (see Clinical Focus, Chapter 5).Monoclonalantibodies also have been used to prepare tumor-specific anti-tumor agents. In this approach, antibodies to tumor-specific or tumor-associated antigens are coupled with radioactive isotopes, chemotherapy drugs, or potent toxins of biological origin. In such “guided missile” therapies, the toxic agents are delivered specifically to tumor cells. This focuses the toxic effects on the tumor and spares normal tissues.Reagents known as immunotoxins have been constructed by coupling the inhibitor chain of a toxin (e.g., diphtheriatoxin) to an antibody against a tumor-specific or tumor-associated antigen (see Figure 4-23). In vitro studies have demonstrated that these “magic bullets” can各种肿瘤的明示显著增加的生长因子受体，它们是抗肿瘤单克隆抗体有希望的目标水平。