Bexxar治疗非霍奇金淋巴瘤的研究现状

B细胞靶向特异性单克隆抗体的出现为惰性淋巴瘤的治疗提供了新的策略。由于淋巴瘤对辐射较为敏感，在过去的10年中，应用131I标记抗-CD20单克隆抗体(商品名：Bexxar)对化疗无效的非霍奇金淋巴瘤(NHL)患进行放射免疫治疗取得了长足的发展。     

非霍奇金B细胞淋巴瘤的放射免疫治疗进展

单克隆抗体的成功应用 ,使肿瘤的放射免疫治疗 (ｒａｄｉｏｉｍ ｍｕｎｏｔｈｅｒａｐｙ,ＲＩＴ)成为可能。由于大多数非霍奇金淋巴瘤 (ＮＨＬ)是ＣＤ2 0阳性的Ｂ细胞淋巴瘤 ,将具有细胞毒性的放射性核素标记的特异性抗ＣＤ2 0单克隆抗体 ,注入体内后可实现对肿瘤细胞的大剂量内照射 ,而正常组织损伤较小 ,大大提高了治疗的缓解率 ,延长了缓解期。1　概　述放射免疫治疗即利用特异性抗体作载体 ,与能释放β或α射线的放射性核素偶合 ,注入体内与肿瘤细胞特异性结合 ,实现对瘤体的内照射治疗。这种治疗多为静脉给药 ,也可局部给药。放射免疫…     

CIK细胞对人原发性胃恶性淋巴瘤生长及肝转移的抑制作用

目的 建立人原发性胃恶性淋巴瘤裸小鼠原位移植肝转移模型,探讨细胞因子诱导的杀伤细胞(CIK)对胃恶性淋巴瘤生长及其肝转移的抑制作用.方法 取原发性胃恶性淋巴瘤患者手术切除的新鲜组织标本,采用外科原位移植技术移植到裸小鼠胃壁黏膜下层,建立人原发性胃恶性淋巴瘤裸小鼠原位移植肝转移模型.应用采血机分离出健康人、胃恶性淋巴瘤患者外周血单个核细胞(PBMC),进行体外培养,通过加入重组人干扰素-γ(rhIFN-γ)、重组人白细胞介素-2(rhIL-2)和抗CD3单克隆抗体(anti-CD3 McAb)刺激,分别制备出CIK细胞和淋巴因子活化的杀伤细胞(LAK).用CIK和LAK细胞实验治疗胃恶性淋巴瘤,对比观察不同来源的两种免疫效应细胞抑制其生长及肝转移的疗效.结果 成功建立了人原发性胃恶性淋巴瘤裸小鼠原位移植肝转移模型.在连续给药20天(0.3ml/d)后,健康人LAK细胞组(2×1010/ml)、健康人CIK细胞组(2×1010/ml)、胃淋巴瘤患者CIK细胞组(1×1010/ml)和胃淋巴瘤患者CIK细胞组(2×1010/ml)的抑瘤率分别为39.28%、53.57%、40.38%、56.42%.生理盐水对照组、健康人LAK细胞组、健康人CIK细胞组、胃淋巴瘤患者CIK细胞组(1×1010/ml)和胃淋巴瘤患者CIK细胞组(2×1010/ml)的肝转移率分别为100.0%、62.5%、50.0%、62.5%、37.5%.结论 人原发性胃恶性淋巴瘤裸小鼠原位移植肝转移模型可用于胃恶性淋巴瘤的发病机制、侵袭、转移及实验治疗的研究.健康人LAK细胞、健康人CIK细胞和胃恶性淋巴瘤患者CIK细胞均具有抑制胃恶性淋巴瘤生长和抗肝转移的作用,且患者来源的CIK细胞抗瘤作用最强.     

放射性核素标记抗CD20单克隆抗体治疗B细胞淋巴瘤的研究进展

放射免疫治疗(radioimmunotherapy,RIT)属于内照射治疗,可以用较少的单克隆抗体耦联放射性核素,在肿瘤局部产生足够的电离辐射生物学效应,达到高效低毒的治疗效果。B细胞淋巴瘤有较高的复发比例,其CD20抗原表达率达90%以上,且不易从细胞膜上脱落,因此131I-利妥昔单抗CD20是B细胞淋巴瘤放免治疗的最佳靶点。目前已有数个放免治疗的药物,如:131I-托西莫单抗(131I-tositumomab)、131I-Rituximab、90Y-替坦异贝莫单抗(90Y-ibritumomabtiuxetan)等,用于B细胞淋巴瘤的临床治疗,它们具有各自的优缺点。使用结果表明:肿瘤部位的高吸收剂量保证了治疗的有效性,其对非靶器官的照射剂量是安全的。最主要的副反应包括:血小板减少症、中性粒细胞减少症、胃肠道反应及甲状腺功能减低症。在取得满意结果的同时,B细胞淋巴瘤放免治疗仍存在许多问题,人们正致力于更进一步的研究解决此类问题,以取得更好的治疗效果。     

用免疫组化方法研究腺淋巴瘤组织起源

腺淋巴瘤的结构是由上皮成分和增生的淋巴组织所组成。对其起源,存在着不同看法,本文作者用抗角蛋白及抗肌动蛋白单克隆抗体,以ABC免疫组化方法探讨腺淋巴瘤组织的起源问题。抗体选择为中间丝     

131I-美罗华治疗难治性复发性B细胞淋巴瘤9例

非霍奇金淋巴瘤 (ＮＨＬ)对常规放化疗较敏感 ,但易出现复发及耐药。单克隆抗体美罗华 (Ｒｉｔｕｘｉｍａｂ)的成功应用成为淋巴瘤治疗领域最重要的进展 ,但仍有部分无效。将单抗与细胞毒性放射性核素连接 ,利用单抗特异性靶向作用和放射性核素所产生的β射线的内照射效应 ,可大大提高治疗的反应率和缓解率。自 2 0 0 1年 10月以来 ,我们应用13 1Ｉ 美罗华治疗难治性复发性Ｂ细胞淋巴瘤 9例 ,取得理想的临床疗效 ,现报道如下。1　资料与方法1 1　临床资料　男性 6例 ,女性 3例 ,年龄 4 5～ 5 9岁 ,平均 5 3岁。 9例均为经多次放化疗后复发的…     

肿瘤放射免疫疗法研究进展

放射免疫治疗是将针对肿瘤特异抗原的单克隆抗体用核素标记后,对肿瘤细胞进行的靶向治疗。在非霍奇金淋巴瘤的临床治疗中,放射免疫治疗已经成为一种常规的治疗手段。在实体瘤中,因为核素标记的单克隆抗体的定位很有限,所以限制了该疗法的使用。虽然如此,放射性核素标记的抗体在治疗微小病灶中的应用前景看好。     

18 F-FDG PET显像对不同亚型淋巴瘤的诊断价值

目的：探讨^18F-脱氧葡萄糖(FDG)PET显像对霍奇金淋巴瘤(HL)和以世界卫生组织(WHO)分类标准分类的不同亚型非霍奇金淋巴瘤(NHL)的诊断价值。方法：对236例淋巴瘤(62例HL和174例NHL)患者的FDG PET全身显像结果进行回顾性分析，并与WHO病理分型的结果比较。结果：PET显像对淋巴瘤的检出阳性率为94％(221／236例)，对HL和NHL的阳性率分别为97％(60／62例)和93％(161／174例)。在不同NHL亚型中，8例套细胞淋巴瘤，99％(76，77例)的弥漫性大B细胞淋巴瘤(DLBCL)，95％(55／58例)的滤泡性淋巴瘤(FL)，73％(8／11例)的淋巴结边缘区淋巴瘤(MZL)，2／3例黏膜相关性(MALL型)结外边缘区B细胞淋巴瘤(MALT-MZL)，5／8例的无其他特征外周T细胞淋巴瘤(PTCL)，2／3例的伯基特淋巴瘤(BL)，2例间变性大细胞性淋巴瘤和覃样肉芽肿、小淋巴细胞性淋巴瘤和NK／T细胞型淋巴瘤各1例FDG摄取异常，而13例(3例MZL，3例PTCL，3例FL，MALT-MZL、DLBCL、BL和前体T淋巴母细胞淋巴瘤各1例)未见异常FDG分布。结论：^18F-FDG PET显像对常见的NHL亚型检出阳性率较高，对相对少见的NHL亚型检出阳性率较低。     

美罗华对人淋巴瘤细胞辐射敏感性的影响

美罗华是一种人鼠嵌合的CD20抗体,是美国食品药品管理局第1个批准用于治疗非霍奇金淋巴瘤的单克隆抗体。大量的体外数据和前临床研究已经证明美罗华增加化疗反应的机制可能与抗体依赖细胞介导的细胞毒作用(ADCC)、补体依赖细胞毒作用(CDC),以及CD20介导的直接跨膜信号导致肿瘤细胞凋亡和生长抑制有关。但是,有不到50%的患者会出现美罗华耐药,所以,寻求新的治疗策略和美罗华作用的机制,对改善淋巴瘤患者的预后十分必要。目前国内尚未见到美罗华在放射治疗中的作用报道,国外可见少数文献报道,但结论有所差异^[1-3]。本研究以耐辐射的人Burkitt淋巴瘤细胞株为研究对象,观察美罗华对其辐射诱导的细胞死亡的影响,并探讨其可能机制。     

原发于纵隔(胸腺)淋巴瘤的MRI诊断

目的 探讨MRI多序列合理应用和动态增强扫描对原发于纵隔(胸腺)淋巴瘤的诊断价值.方法 对9例病理证实的原发于纵隔(胸腺)淋巴瘤的MRI表现进行了回顾性分析,并与胸腺瘤(癌)进行鉴别,归纳总结原发于纵隔(胸腺)淋巴瘤的MRI特征性表现.结果 9例原发性胸腺淋巴瘤中2例为霍奇金淋巴瘤(HL),5例为弥漫性大B细胞淋巴瘤,2例为前驱T细胞淋巴母细胞淋巴瘤/白血病.与胸腺上皮源性肿瘤比较:①淋巴瘤发病年龄明显较胸腺瘤、胸腺癌轻,为(29.7±17.0)岁.②肿瘤边缘模糊征象,淋巴瘤发生率与胸腺上皮源性肿瘤差异无统计学意义.③本组1例淋巴瘤可见假包膜,胸腺上皮源性肿瘤未见此征象;④分叶征,淋巴瘤发生率明显高于胸腺瘤,而与胸腺癌无明显差异.⑤延迟期"边缘环形强化"征象,淋巴瘤发生率高于胸腺瘤及胸腺癌.其他征象差异无明显统计学意义.结论 MRI 多种序列及动态增强扫描综合应用在对原发性胸腺淋巴瘤诊断方面具有一定价值.     

单链抗体研究进展及其在医学中的应用

自英国和日本学者发现白喉抗毒素以来,人们对于抗体的研究经历了多克隆抗体、单克隆抗体和基因工程抗体3个阶段,其中单链抗体由于具有相对分子质量小、穿透力强、血中半衰期短、抗原结合特异性强、免疫原性弱和可在原核细胞中表达等特点而倍受人们关注。     

红斑狼疮(SLE和DLE)抗核抗体、抗ENA抗体和抗dsDNA抗体的检测及意义

目的：探讨抗核抗体（ANA）、抗ENA抗体和抗dsDNA抗体在红斑狼疮（SLE和DLE）的实际临床实用价值和特点。方法：ANA和抗dsDNA抗体采用间接免疫荧光检测，ANA检测灵长类动物的肝组织印片和人类上皮细胞（Hep-2细胞）为抗原底物，抗dsDNA抗体的实验基质为血鞭毛虫属的绿蝇短膜虫。抗ENA抗体检测采用酶免疫斑点（条带）实验。结果：ANA在SLE患者阳性率为90．4％，DLE患者为75．0％，dsDNA阳性率为63．5％，ENA总阳性率为84．5％。结论：ANA是诊断红斑狼疮的重要指标，但与病情活动性平行关系，抗dsDNA抗体是SLE活动的重要标志。     

Development of a stable radioiodinating reagent to label monoclonal antibodies for radiotherapy of cancer

A method of radioiodinating monoclonal antibodies such that the labeled antibodies do not undergo in vivo deiodination has been studied. The method utilizes conjugation of succinimidyl para-iodobenzoate to the antibody. The iodobenzoate was radiolabeled by using an organometallic intermediate to facilitate the reaction. Thus, succinimidyl para-tri-n-butylstannylbenzoate was radiolabeled in 60-90% radiochemical yield and subsequently conjugated to the antibody in 80-90% yield. Animal biodistribution studies were carried out with two separate anti-melanoma antibodies (9.2.27 and NR-M1-05) labeled by this method, and examined in nude mice bearing human melanoma tumor xenografts. Very large differences in the localization of radioactivity were observed in the thyroids and stomachs of mice when the iodobenzoyl-labeled antibodies were compared with the same antibodies labeled using the chloramine-T method of radioiodination. Few other significant differences in the tissue distribution of the radioiodinated antibodies were seen.     

Imaging of lesions in a murine rheumatoid arthritis model with a humanized anti-interleukin-6 receptor antibody

Rheumatoid arthritis (RA) has been attributed to the abnormal production of cytokine interleukin-6 (IL-6), which has a variety of physiological activities. In vivo IL-6-receptor imaging provides useful suggestions regarding the mechanism of anti-IL-6-receptor antibody action and indicates a basic therapeutic strategy for treating RA. Therefore, this study was designed to establish a method for radiolabeling anti-IL-6-receptor antibodies and to investigate the feasibility of using radiolabeled anti-IL-6-receptor antibodies in the scintigraphic imaging of lesions in an animal RA model. Anti-IL-6-receptor antibodies were conjugated with a bifunctional chelating agent, hydrazinonicotinamide (HYNIC), and radiolabeled with technetium-99m (99mTc) using the ligand exchange reaction of 99mTc-tricine complex. The binding affinity was estimated using the U266 cell line. Whole body scintigraphy, biodistribution and autoradiography were undertaken in mice containing synovial cells that had been transplanted from an RA patient. Our findings showed that the antibodies accumulated in the implanted tissue. When radiolabeled anti-IL-6-receptor antibodies are used in scintigraphic imaging, the distribution of the IL-6-receptors is associated with the inflammatory cell infiltration that is seen in the early stage of RA. Accordingly, imaging with humanized anti-IL-6-receptor antibodies appears to be useful for detecting early pathophysiological conditions and assessing the efficacy of antibody treatment as well as the prognosis of patients with RA.     

Recent developments in the radiolabeling of antibodies with iodine, indium, and technetium

The use of radiolabeled antibodies for tumor detection and therapy has provided some striking successes despite unfavorable tumor-to-normal tissue radioactivity ratios due, in part, to the accumulation of the label in normal tissues. One approach, which has been and is still under consideration to reduce unwanted background levels, is the improvement of ways in which radiolabels are attached to antibody, especially with the goal of increasing in vivo stability. Although these improvements have occurred throughout the history of this field, important developments have recently been reported in the labeling of antibodies with three radiolabels, namely radioiodine, 111In, and 99mTc. Thus, antibodies may now be labeled with radioisotopes of iodine in ways that minimize the extent of in vivo dehalogenation leading to thyroid, stomach, and gut radioactivity uptake. Newer and stronger chelates for 111In have been developed in the hope that their use would result in lower radioactivity levels in the liver. Finally, newer methods, both direct and indirect, for the attachment of 99mTc to antibodies have been developed and are now being clinically tested. Although these developments have taken place only recently and the in vivo behavior of labels attached in these ways have not yet been fully characterized, it is possible to make tentative conclusions regarding their impact. Thus, the use of stably radioiodinated antibodies appears to have resulted in modest improvements in patient images. In contrast, the use of stable chelates for labeling antibodies with 111In may have had no appreciable effect on liver radioactivity levels. The use of antibodies radiolabeled with 99mTc, especially via the newer direct labeling methods, are providing superior images in patients with low radioactivity levels in organs such as liver. However, it must still be established whether the short physical half-life of 99mTc lowers sensitivities and specificities of detection relative to other labels.     

Variations in radioimmunoscintigraphic detection of tumor showed by five monoclonal antibodies to carcinoembryonic antigen

Radioimmunoscintigraphy using mouse monoclonal antibodies to various parts of a carcinoembryonic antigen (CEA) molecule was performed. Four radiolabeled antibodies (F4-82, 28A, F3-30, F33-104) were injected into tumor transplanted nude mice to compare the accumulation of these antibodies in tumors. The four antibodies were accumulated selectively in CEA- producing tumors. The tumor visualization correlated with the tumor/blood radioactivity ratio, whereas the tumor/blood radioactivity ratio did not correlate with the in vitro percent binding to tumor cells or the in vivo percent injected dose in CEA-producing tumors. Among the four antibodies, F33-104 showed the highest tumor/blood radioactivity ratio and the best image quality in any CEA-producing tumor. These results suggest that the antibody which has a high tumor/blood ratio rather than high total tumor uptake may be useful for radioimmunoscintigraphy.     

Antibody and radionuclide characteristics and the enhancement of the effectiveness of radioimmunotherapy by selective dose delivery to radiosensitive areas of tumour

Purpose : Estimating the absorbed dose to tumour relative to normal tissues has often been used in the assessment of the therapeutic efficacy of radiolabelled antibodies for radioimmunotherapy. Typically, the calculations assume a uniform dose deposition and response throughout the tumour. However, the heterogeneity of the dose delivery and response within tumours can lead to a radiobiological effect inconsistent with dose estimates. The aim was to assess the influence of antibody and radionuclide characteristics on the heterogeneity of dose deposition. Materials and methods : Quantitative images of the temporal and spatial heterogeneity of a range of antibodies in tumour were acquired using radioluminography. Subsequent registration with images of tumour morphology then allowed the delineation of viable and necrotic areas of tumour and the measurement of the antibody concentration in each area. A tumour dosimetry model then estimated the absorbed dose from 131 I and 90 Y in each area. Results : Tumour-specific antibodies initially localized in the viable radiosensitive areas of tumour and then penetrated further into tumour with continued tumour accretion. Multivalent antibodies were retained longer and at higher concentrations in viable areas, while monovalent antibodies had greater mobility. In contrast, non-specific antibodies penetrated into necrotic regions regardless of their size. As a result, multivalent, specific antibodies delivered a significantly larger dose to viable cells compared with monovalent antibodies, while non-specific antibodies deposited most of the dose in necrotic areas. There was a significant difference in dose estimates when assuming a unifrom dose deposition and accounting for heterogeneity. The dose to the viable and necrotic areas also depended on the properties of the radionuclide where antibodies labelled with 131 I generally delivered a higher dose throughout the tumour even though the instantaneous dose-rate distribution for 90 Y was more uniform. Conclusions : The extent of heterogeneity of dose deposition in tumour is highly dependent on the antibody characteristics and radionuclide properties, and can enhance therapeutic efficacy through the selective dose delivery to the radiosensitive areas of tumour.     

基因工程双特异性抗体构建模式研究进展

为了增强抗体的效应功能，人们尝试多种方法改造抗体分子，双特异性抗体是改善抗体治疗效果的发展方向之一，现已成为抗体工程研究领域的热点。随着分子生物学技术的迅速发展，出现了基因工程双特异性抗体的多种构建模式，并且有多种基因工程双特异性抗体制剂已经用于肿瘤的临床诊断和治疗试验。本文对基因工程双特异性抗体的构建模式按照双特异性微抗体、双链抗体、单链双特异性抗体和多价双特异性抗体4类进行了综述。     

Antibody imaging in the evaluation of cardiovascular diseases

Antimyosin antibody was originally developed for in vivo detection of acute myocardial infarction. However, its utility has expanded to include diagnosis of various cardiovascular diseases in which myocyte necrosis constitutes an obligatory component of the disease. Thus antimyosin has also been used clinically for noninvasive diagnosis of acute myocarditis, heart transplant rejection, drug-induced cardiotoxicity, and other cardiomyopathies. This firstgeneration monoclonal antibody, antimyosin, has opened the way for the second-generation monoclonal antibodies such as antifibrin and antiplatelet for in vivo diagnostic use in the detection of deep venous thrombosis and pulmonary embolism and antiatherosclerotic lesion-specific antibody for diagnosis of metabolically active lesions. Whether the third generation of antibodies will include ultrasmall antigen-binding units or negative chargemodified antibodies must await future studies. An erratum to this article is available at .