131Ⅰ-rituximab治疗B细胞非霍奇金淋巴瘤

放射免疫治疗是将单克隆抗体(单抗)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.非霍奇金淋巴瘤(NHL)是最常见的淋巴系统恶性肿瘤之一,其绝大多数是B细胞来源,细胞分化抗原CD20是放射免疫治疗B细胞NHL的最佳靶点,用131Ⅰ标记rituximab(一种抗CD20单抗)在治疗B细胞NHL的临床研究中显示出良好的效果,但仍存在许多问题,人们正在进一步研究解决此类问题,以取得更好的治疗效果.     

利妥昔单抗免疫化疗联合自体外周血干细胞移植治疗CD20+B细胞性非霍奇金淋巴瘤的临床研究

目的 分析和探讨利妥昔单抗联合自体外周血造血干细胞移植(APBSCT)序贯维持治疗对CD20+B细胞非霍奇金淋巴瘤(NHL)的疗效.方法 搜集2005年1月—2011年1月诊断为侵袭性和(或)难治复发性CD20+B细胞NHL并接受APBSCT治疗的60例患者的临床资料.分为2组:治疗组(n=25),APBSCT前应用利妥昔单抗3～4次,采集自体干细胞前1d加用利妥昔单抗治疗1次(375mg/m2)体内净化干细胞,移植后每3～6个月应用利妥昔单抗联合白细胞介素-2(100万U/次,缓慢静滴)维持治疗3～4次;对照组35例,除未用利妥昔单抗以外,其他处理与治疗组相同.结果 利妥昔单抗在移植前、干细胞采集前及移植后巩固治疗中均未发现明显不良反应.治疗组和对照组采集单个核细胞数分别为(8.2±2.9)×108/kg和(8.4±3.9)×108/kg(P=0.822),CD34+细胞数分别为(12.3±12.7)×106/kg和(13.2±13.9)×106/kg(P=0.799).治疗组均顺利完成造血重建,对照组3例造血重建失败.两组中性粒细胞恢复时间和血小板恢复时间差异无统计学意义.移植后所有病例均达完全缓解(CR),中位随访22(2 ～ 81)个月,治疗组2例复发,对照组6例复发.治疗组3年总体生存率有高于对照组的趋势(91.6％ vs 69.5％,P=0.060).结论 侵袭性和(或)难治复发性CD20+B细胞NHL患者APBSCT前后应用利妥昔单抗不影响造血干细胞的采集和造血重建,且有望提高治疗效果、改善总体生存.     

利妥昔单抗联合化疗治疗CD20+的B细胞型非霍奇金淋巴瘤

利妥昔单抗 (美罗华 ,rituximab ,罗氏制药公司 )是通过基因重组技术生产的一种小鼠_人嵌合抗CD2 0单克隆抗体 ,对初治或复发的惰性CD2 0 + 非霍奇金淋巴瘤 (NHL)有很好的疗效 ,并对其他B细胞功能异常疾病亦展示较好的治疗前景。国外目前已有多组病例研究 ,但国内报道尚少。我科2 0 0 1年 6月至 2 0 0 2年 8月共有 9例B细胞型NHL患者应用利妥昔单抗联合化疗 ,现报告如下。1　材料与方法1.1　一般资料9例患者均为CD2 0 + B细胞NHL患者 ,中位年龄 4 5岁(12～ 5 7岁 ) ,其中男性 7例 ,女性 2例。采用AnnArbor_Col swolds临床分期标准 …     

免疫PET/SPECT显像:精准医学时代伴随诊断新范式

1987年王世真和施绪保撰文指出:"当前核医学有两个最重要的前沿性科学研究新方向,一个是正电子发射断层技术,另一个是放射免疫显像和治疗。"几十年来,随着单克隆抗体(简称单抗)工程化制备技术的成熟,全球大量单抗药物的快速发展和临床应用,以及PET和SPECT等高灵敏显像技术的广泛应用和普及,放射免疫显像已被赋予新的内涵和功能。基于放射性核素标记单抗及其衍生物探针的免疫PET显像和免疫SPECT显像(ImmunoPET/SPECT)等分子显像技术,可以无创可视化抗体药物在肿瘤组织中的特异性摄取和在正常组织中的分布,发现同一患者不同区域病灶或同一病灶内部靶点的异质性表达,预测和评估靶向治疗或免疫治疗方案的有效性及毒性和不良反应。目前,大量ImmunoPET/SPECT显像技术已经完成探针制备与临床前评估等研究,有待或已逐步进入临床实践,成为前沿性科学研究和临床转化的热点。     

靶向CD30单克隆抗体64Cu-NOTA-CD30的淋巴瘤免疫PET显像研究

目的制备靶向CD30单克隆抗体(简称单抗)64Cu-1, 4, 7-三氮杂环壬烷-1, 4, 7-三乙酸(NOTA)-CD30, 无创性可视化评价淋巴瘤CD30的表达。方法通过Western blot评价5种淋巴瘤细胞株(Karpas299、Raji、Daudi、Ramos和U266)中CD30的表达水平。选择高和低表达CD30的细胞株行流式细胞术评估抗CD30单抗特异性结合能力。取NSG小鼠13只构建CD30阳性和阴性皮下荷瘤鼠模型。标记获得64Cu-NOTA-CD30, 以64Cu-NOTA-免疫球蛋白(Ig)G为对照探针。经尾静脉注射2种探针后2、24和48 h行microPET显像及生物分布分析。采用重复测量方差分析及Bonferroni法进行数据比较。结果 Karpas299细胞呈CD30高表达, Raji细胞呈CD30低表达。流式细胞术示抗CD30单抗与Karpas299细胞特异性结合。64Cu-NOTA-CD30与64Cu-NOTA-IgG的放化纯均>95%。在microPET显像中, Karpas299肿瘤64Cu-NOTA-CD30摄取随时间延长逐渐升高, 2、...     

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。     

非霍奇金淋巴瘤针吸细胞学与免疫表型观察

目的：探讨针吸细胞学（FNAC）及免疫表型在非霍奇金淋巴瘤（NHL）诊断中的价值。方法：运用针吸细胞学和免疫组化标记技术对19例NHL淋巴结进行观察研究。结果：19例（B-NHL12例，T-NHL7例）NHL中，FNAC诊断16例，诊断准确率84．2％（16A4），3例可疑病例结合免疫组化标记技术结果与病理组织完全一致，诊断符合率100％（36）。免疫表型：T细胞性CB、CD45BC）阳性，B细胞性CD20、CD79。阳性，T、B细胞CD68、CK和EMA均为阴性。结论：FNAC辅以免疫组化技术，是一种方便快捷，经济有效的NHL诊断方法。     

67Ga显像对淋巴瘤治疗的监测

目的用67Ga显像预测和监测非霍奇金淋巴瘤(NHL)治疗后的早期疗效.方法86例治疗前67Ga显像和CT扫描阳性的淋巴瘤患者,经临床和病理检查证实为NHL.平面67Ga显像分别在治疗后2和4个疗程进行.有51例患者治疗4个疗程后进行CT扫描.患者经4个疗程治疗后,平均随访时间为1.5年(3～30个月).治疗效果评价①完全有效病灶不显影;②部分有效病灶部分显影;③无效病灶显影无变化或进一步增大.结果86例患者中61例67Ga显像示治疗完全有效,14例部分有效,11例治疗无效.随访中,早期67Ga显像阴性预测值90%(43/48例),晚期67Ga显像阴性预测值69%(9/13例),提示前者更有临床价值.病灶部分消失和无变化者,阴性预测值仅36%(9/25例),提示这部分患者预后很差.CT结果治疗后,51例患者中18例阴性,33例阳性,随访中,阴性预测值67%(12/18例),而阳性预测值为27%(9/33例).表明67Ga显像能有效预测疗效(P<0.001),而CT则不能(P>0.05).结论治疗后早期67Ga显像对预测和检测NHL疗效优于晚期显像,对患者治疗疗效的评价明显优于CT.     

钙离子内流参与利妥昔单抗增强辐射诱导的Raji细胞凋亡

钙离子是细胞生命活动的重要信使,刺激B细胞受体可诱导细胞内钙库的损耗,导致质膜上调控钙库的钙通道激活。已经发现,随着游离钙离子稳态被打破以及CD20与其单克隆抗体（利妥昔单抗）偶联,可导致细胞凋亡。细胞转染CD20后,可增加钙离子通过质膜进入细胞内,证明CD20具有调节细胞周期进程和作为钙离子通道平衡细胞内外钙浓度的功能。在Ramos B细胞中,src家族蛋白酪氨酸激酶的CD20调节刺激提高了细胞内钙离子浓度,并且诱导了Caspase 3的活性。除此之外,利妥昔单抗诱导的CD20和脂筏的高亲和性是钙进入细胞和激活下游凋亡信号的先决条件,与B细胞抗原受体的表达密切相关。在淋巴瘤细胞系中,利妥昔单抗联合辐射能显著提高辐射诱导细胞凋亡,利妥昔单抗通过改变细胞程序性死亡相关蛋白的表达、提高细胞内ROS水平、调节细胞周期等提高淋巴瘤细胞的辐射敏感性。然而,钙离子是否参与辐射和CD20靶向诱导细胞死亡尚不明确。闵凤玲等的“Influx of extracellular calcium participates in rituximab-enhanced ionizing radiation-induced apoptosis in Raji cells”一文,研究了利妥昔单抗和X射线照射后,淋巴瘤细胞内钙离子水平变化与DNA双链断裂和辐射诱导细胞死亡的关系,探讨了利妥昔单抗在辐射诱导细胞死亡中的作用机制。     

原发性肝脏黏膜相关边缘区B细胞淋巴瘤的诊断(附1例报告并文献复习)

目的提高对原发性肝脏黏膜相关边缘区B细胞淋巴瘤(MALT)的认识,探讨诊治方法。方法回顾性分析1例以午后间歇性低热、盗汗为首发表现的原发性肝脏MALT患者的临床资料,并通过复习相关文献,总结诊治经验。结果原发性肝脏MALT患者的临床表现无特异性,影像学检查易误诊为原发性肝癌。本例患者在排除肝内结核和原发性肝癌的基础上,行经皮CT引导下穿刺活检。标本的免疫组化检查示:Ki-67增殖活性15%～20%,CD20、CD79a、Bcl-2和PaX-5阳性,CD5、CD10、CD3、CD7、CD23、CD43、MUM1及cyclinD1阴性。根据病理学检查结果 (典型的淋巴上皮病变)可确诊原发性肝脏MALT。给予利妥昔单抗联合氟达拉滨方案化疗6个疗程,患者获得完全缓解,随访至2010-04-21已存活12个月。回顾性分析文献中49例原发性肝脏MALT,患者中位发病年龄62(36～85)岁,男∶女为0.91∶1。影像学检查以孤立性病变较多见,氟-18标记的氟代脱氧葡萄糖正电子断层显像-CT(18F-FDGPET-CT)扫描有助于对肝脏MALT淋巴瘤进行分期。手术治疗是最常用的治疗方法 ,推荐在行手术治疗后联合化疗或免疫治疗。结论原发性肝脏MALT罕见,起病隐匿,临床表现不典型,确诊主要依靠组织病理学结果和免疫表型特征,淋巴细胞IgH基因重排和染色体易位检测等遗传学和分子生物学检查是重要的辅助检查手段。     

Current status of cancer therapy with radiolabeled monoclonal antibody

Molecular targeting therapy has become a relevant therapeutic strategy for cancer. There are several monoclonal antibodies used for the treatment of malignant tumors. Radioimmunoconjugate is composed of antibody and radionuclide showing a synergistic effect of radiation and immunemediated cellular toxicity and thereby enabling increased efficacy and minimizing toxicity. Radioimmunotherapy using 131I- and 90Y-labeled anti-CD20 monoclonal antibodies is now indicated for the treatment of patients with CD20 antigen-expressing relapsed or refractory, low-grade or transformed non-Hodgkin's lymphoma (NHL), including patients who are refractory to anti-CD20 monoclonal antibody (rituximab) therapy in the United States. It has been exhibiting favorable anti-tumor efficacy in patients with NHL as compared with rituximab. Myelosuppression is the main side effect associated with the radioimmunotherapy but is usually reversible, and nonhematologic adverse reactions are mild to moderate. Following the impressive results of therapy using radiolabeled monoclonal antibodies for NHL, radioimmunotherapy for solid tumors has been examined; however, the results were unfavorable and did warrant further clinical trials as a single agent. Future studies on radioimmunotherapy for solid tumors should focus on the new strategies of targeting such as locoregional administration for intraperitoneal dissemination, and combination therapy with chemotherapy or cytostatic therapy. Although radioimmunotherapy for NHL has shown excellent results comparable to aggressive chemotherapy without severe adverse effects, additional clinical trials should be performed to define the proper role of radioimmunoconjugates as a relevant strategy for cure of NHL.     

Treatment of non-Hodgkin's lymphoma (NHL) with radiolabeled antibodies (mAbs)

Most patients with non-Hodgkin's lymphoma (NHL) achieve remission but, despite newer drugs, the natural history of this disease has not improved during the last 20 years. Less than one half of patients with aggressive NHL are cured, and few of those with low-grade NHL are curable. Furthermore, NHL becomes progressively more chemoresistant while remaining responsive to external beam radiation therapy. Radioimmunotherapy (RIT) is a logical strategy for the treatment of NHL because this disease is multifocal and radiosensitive. Because of their remarkable effectiveness for RIT, 2 anti-CD20 monoclonal antibodies (mAbs), one labeled with (111)In for imaging or (90)Y for therapy and a second labeled with (131)I for imaging and therapy, have been approved for use in patients with NHL. These drugs have proven remarkably effective and safe. Evidence for the importance of the radionuclide is manifested by the data in the randomized pivotal phase III trial of (90)Y-ibritumomab that revealed response rates were several times greater in the (90)Y-ibritumomab arm than in the rituximab arm. A second drug for RIT, (131)I-tositumomab, was compared in a pivotal trial with the efficacy of the last chemotherapy received by each patient. Once again, response rates were much higher for RIT. Both (90)Y-ibritumomab and (131)I-tositumomab require preinfusion of several hundred milligrams of unlabeled anti-CD20 mAb to obtain "favorable" biodistribution, that is, targeting of NHL. Response rates for other mAbs and radionuclides in NHL also have been high but these drugs have not reached the approval stage. These drugs can be used safely by physicians who have suitable training and judgment. Unlike chemotherapy, RIT is not associated with mucositis, hair loss, or persistent nausea or vomiting. Although hematologic toxicity is dose limiting, hospitalization for febrile neutropenia is uncommon. Randomized trials of RIT in different formulations have not been conducted, but there is evidence to suggest that the mAb, antigen, radionuclide, chelator, linker, and dosing strategy may make a difference in the outcome.     

Correlation of marrow dose estimates based on serial pretreatment radiopharmaceutical imaging and blood data with actual marrow toxicity in anti-CD20 yttrium-90 monoclonal antibody radioimmunotherapy of non-Hodgkin's B-cell lymphoma

The purpose of this study was to investigate whether marrow radiation absorbed dose estimates predict haematotoxicity following radioimmunotherapy with an yttrium-90 labelled anti-CD20 monoclonal antibody in non-Hodgkin's B-cell lymphoma (NHL). Radiopharmaceutical data from 12 NHL radioimmunotherapy patients were analysed retrospectively using three methods of marrow radiation absorbed dose estimation based on serial pretreatment indium-111 labelled anti-CD20 monoclonal antibody activity versus time data (0-144 h): (i) lumbar spine (LS) image counts; (ii) blood clearance (BL); and (iii) whole body (WB) activity. Linear regressions were performed between the methods, and between each method and the 0-6 month post-treatment platelet and white blood cell count nadir and absolute drop in count (ADC). For the range of yttrium-90 activities (740-1547 MBq), absorbed dose estimates (mean +/- sigma) were: LS, 142+/-50 cGy (range 62-233 cGy); BL, 89+/-21 cGy (range 63-140 cGy); and WB, 54+/-10 cGy (range 36-63 cGy). The LS and BL marrow estimates differed significantly (P <0.003), with a correlation coefficient r of 0.36 (P = NS), while WB correlated significantly with both LS (r = 0.50, P < 0.05) and BL (r = 0.58, P < 0.05). The range of r with platelet nadir and ADC was -0.20 < or = r < or = 0.01, except for WB with ADC (r = 0.38) (all P = NS). Values of r for white blood cell nadir were unexpectedly positive, being 0.13 for BL and 0.29 for LS (P = NS), and 0.60 for WB (P < 0.025). Values of r for white blood cell ADC were 0.36 for BL and -0.26 for LS (P = NS), and 0.50 for WB (P < 0.05). These results indicate that different commonly employed methods of estimating marrow radiation absorbed dose may yield significantly differing results, which may not correlate with actual radiation toxicity. Therefore, caution must be exercised in relying on these results to predict haematotoxicity.     

Biodistribution and kinetics of (131)I-labelled anti-CD20 MAB IDEC-C2B8 (rituximab) in relapsed non-Hodgkin's lymphoma

The native chimeric human-mouse anti-CD20 antibody IDEC-C2B8 (rituximab) is therapeutically applied in relapsed non-Hodgkin's lymphoma (NHL). The purpose of this study was to evaluate the distribution and pharmacokinetics of iodine-131 labelled rituximab in humans for radioimmunotherapy of relapsed CD20-positive NHL. Thirty-five patients with relapsed NHL were administered 20-40 mg rituximab labelled with 250 MBq (131)I. Biodistribution was determined by the gamma camera whole-body scans, whole-body probe measurements and the analysis of serial blood and urine samples. Dosimetry was performed using the MIRDOSE 3 program. Antibody administration was well tolerated. The whole-body activity showed a mono-exponential decrease with a wide range of effective half-lives, the mean value (88 h) being significantly longer than the half-life of its murine counterpart, tositumomab. This led to appropriately higher dose factors for the whole body and organs. Activity was excreted mainly through the kidneys. Normal organs showed decreasing ratios of organ to whole-body activity over time, whereas the tumour tissue presented different kinetics, with increasing ratios of tumour to whole-body activity as evidence for specific antibody binding. It is concluded that (131)I-labelled rituximab is suitable for pretherapeutic dosimetry. Due to the wide range of whole-body and organ dose factors, individual dosimetry is necessary for radioimmunotherapy with (131)I-labelled rituximab. The therapeutic activities of (131)I-labelled rituximab required to deliver similar doses should be lower than those of its murine counterpart.     

Radioimmunotherapy of B-cell non-Hodgkin's lymphoma: from clinical trials to clinical practice.

Radioimmunotherapy (RIT) is a new treatment modality for B-cell non-Hodgkin's lymphoma (NHL). Recent clinical trials have clearly established its efficacy in NHL patients refractory to standard chemotherapy or immunotherapy with the widely used unconjugated rituximab monoclonal antibody (mAb). The Food and Drug Administration has approved (90)Y-ibritumomab tiuxetan anti-B-cell NHL mAb as the first commercially available radiolabeled antibody for cancer therapy. This comes only a few years after the introduction of rituximab into clinical practice as the first unconjugated antibody for cancer treatment, underscoring the success of both immunotherapy and RIT in the treatment of NHL. With the approval of (90)Y-ibritumomab tiuxetan, and based on the results of numerous clinical trials with radiolabeled anti-B-cell NHL mAbs, RIT promises to become integral to nuclear medicine practice. In this article, the basic concepts of RIT are reviewed with important milestones in its development for B-cell NHL treatment and particular emphasis on phase II and III clinical trials establishing its efficacy in clearly defined patient populations. Finally, the prospects for the expected widespread clinical use of RIT in the management of B-cell NHL, alone or in combination with other more established therapies, are discussed. This article provides both investigative and clinical nuclear medicine physicians with a better understanding of RIT capabilities and limitations in B-cell NHL and their role as consultants in the care of NHL patients.     

In vitro evaluation of radioprotective and radiosensitizing effects of rituximab.

Clinical radioimmunotherapies with anti-CD20 monoclonal antibodies involve administering a predose of unlabeled anti-CD20 antibodies to favorably alter the biodistribution profile of the subsequently administered radiolabeled antibodies and mediate antitumor effects. Prior in vitro data suggested that unlabeled anti-CD20 monoclonal antibodies radiosensitize lymphoma cells as well. We assessed the antiproliferative and possible radiosensitizing capabilities of an anti-CD20 monoclonal antibody, rituximab. METHODS: Luciferase-transfected (via a lentivirus vector) CD20+ human Raji lymphoma cells in log-phase growth were incubated with or without rituximab (20 microg/mL) for either 1 or 24 h before external-beam radiation exposure. Cell counts were measured with a luciferase assay at 24-h intervals. Subsets of these cells were also analyzed for cell cycle status by flow cytometry. RESULTS: Rituximab pretreatment and irradiation were found to significantly inhibit tumor cell growth compared with irradiation alone (by a factor of 0.40 at 1 Gy [P < 0.01]). One hour of rituximab pretreatment modestly radiosensitized tumor cells at a radiation dose of 1 Gy (by a factor of 1.03 compared with the results for nonirradiated cells). At higher radiation doses (2 and 12 Gy), 1 h of rituximab pretreatment paradoxically radioprotected tumor cells by factors of 0.25 (P < 0.01) and 0.54 (P < 0.05), respectively. Rituximab predosing for 24 h was found to be radiosensitizing at a radiation dose of 4 Gy (by a factor of 2.84 [P < 0.01]) but radioprotective at radiation doses of 1, 8, and 12 Gy (by factors of 0.10 [P < 0.01], 2.50 [P < 0.01], and 2.07 [P < 0.05], respectively). These results correlated with retardation of the cell cycle at 6 d after rituximab administration, as determined by flow cytometry. CONCLUSION: Rituximab demonstrated a direct tumor antiproliferative effect in the absence of radiation. At lower levels of radiation exposure, rituximab radiosensitized Raji lymphoma cells. At higher doses of radiation, rituximab paradoxically protected tumor cells against ionizing radiation, possibly through effects on the cell cycle. These radiobiologic effects of rituximab should be carefully considered in the design of radioimmunotherapeutic trials.     

In vitro characterization of <Superscript>177</Superscript>Lu-radiolabelled chimeric anti-CD20 monoclonal antibody and a preliminary dosimetry study

Purpose   ¹³¹I- and ⁹⁰Y-labelled anti-CD20 antibodies have been shown to be effective in the treatment of low-grade, B-cell non-Hodgkin’s lymphoma (NHL). However, the most appropriate radionuclide in terms of high efficiency and low toxicity has not yet been established. In this study we evaluated an immunoconjugate formed by the anti-CD20 antibody rituximab and the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). DOTA-rituximab was prepared as a kit formulation and can be labelled in a short time (<20 min) with either ¹⁷⁷Lu or ⁹⁰Y. Materials and methods  Immunoconjugates with different numbers of DOTA molecules per rituximab were prepared using p-SCN-Bz-DOTA. In vitro immunoreactivity and stability were tested and preliminary dosimetric results were acquired in two patients. Results  The immunological binding properties of DOTA-rituximab to the CD20 antigen were found to be retained after conjugation with up to four chelators. The labelled product was stable against a 10⁵ times excess of diethylenetriaminepentaacetic acid (DTPA, 37°C, 7 days). Two patients with relapsed NHL were treated with 740 MBq/m² body surface ¹⁷⁷Lu-DOTA-rituximab. Scintigraphic images showed specific uptake at tumour sites and acceptable dosimetric results. The mean whole-body dose was found to be 314 mGy. The administration of ¹⁷⁷Lu-DOTA-rituximab was tolerated well. Conclusion  Our results show that DOTA-rituximab (4:1) can be labelled with ¹⁷⁷Lu with sufficient stability while the immunoconjugate retains its immunoreactivity. ¹⁷⁷Lu-DOTA-rituximab is an interesting, well-tolerated radiolabelled antibody with clinical activity in a low dose range, and provides an approach to the efficient treatment with few side effects for patients with relapsed NHL. Flavio Forrer and Jianhua Chen contributed equally to this work.     

99mTc-rituximab radiolabelled by photo-activation: a new non-Hodgkin’s lymphoma imaging agent

Purpose Rituximab was the first chimeric monoclonal antibody to be approved for treatment of indolent B-cell non-Hodgkins lymphoma (NHL). It is directed against the CD20 antigen, which is expressed by 95% of B-cell NHLs. The aim of this study was to explore the possibility of radiolabelling rituximab with ^99mTc for use as an imaging agent in NHL for early detection, staging, remission assessment, monitoring for metastatic spread and tumour recurrence, and assessment of CD20 expression prior to (radio)immunotherapy.Methods Rituximab was purified from Mabthera solution (Roche), photo-activated at 302 nm by UV irradiation and radiolabelled with ^99mTc. The effectiveness of the labelling method was evaluated by determination of the number of free thiol groups per photoreduced antibody, radiochemical purity and in vitro stability of ^99mTc-rituximab.Results On average, 4.4 free thiol groups per photoreduced antibody were determined. Radiolabelling yields greater than 95% were routinely observed after storage of the photo-activated antibody at –80°C for 195 days. The direct binding assay showed preserved ability of ^99mTc-rituximab to bind to CD20, with an average immunoreactive fraction of 93.3%. The internalisation rate was proven to be low, with only 5.3% of bound ^99mTc-rituximab being internalised over 4 h at 37°C.Conclusion Our results demonstrate that ^99mTc-rituximab of high radiochemical purity and with preserved binding affinity for the antigen can be prepared by photoreduction and that the method shows good reproducibility. ^99mTc-rituximab will be further explored as an imaging agent applicable in NHL for the purposes mentioned above.     

Molecular imaging of rheumatoid arthritis by radiolabelled monoclonal antibodies: new imaging strategies to guide molecular therapies

The closing of the last century opened a wide variety of approaches for inflammation imaging and treatment of patients with rheumatoid arthritis (RA). The introduction of biological therapies for the management of RA started a revolution in the therapeutic armamentarium with the development of several novel monoclonal antibodies (mAbs), which can be murine, chimeric, humanised and fully human antibodies. Monoclonal antibodies specifically bind to their target, which could be adhesion molecules, activation markers, antigens or receptors, to interfere with specific inflammation pathways at the molecular level, leading to immune-modulation of the underlying pathogenic process. These new generation of mAbs can also be radiolabelled by using direct or indirect method, with a variety of nuclides, depending upon the specific diagnostic application. For studying rheumatoid arthritis patients, several monoclonal antibodies and their fragments, including anti-TNF-α, anti-CD20, anti-CD3, anti-CD4 and anti-E-selectin antibody, have been radiolabelled mainly with ^99mTc or ¹¹¹In. Scintigraphy with these radiolabelled antibodies may offer an exciting possibility for the study of RA patients and holds two types of information: (1) it allows better staging of the disease and diagnosis of the state of activity by early detection of inflamed joints that might be difficult to assess; (2) it might provide a possibility to perform ‘evidence-based biological therapy’ of arthritis with a view to assessing whether an antibody will localise in an inflamed joint before using the same unlabelled antibody therapeutically. This might prove particularly important for the selection of patients to be treated since biological therapies can be associated with severe side-effects and are considerably expensive. This article reviews the use of radiolabelled mAbs in the study of RA with particular emphasis on the use of different radiolabelled monoclonal antibodies for therapy decision-making and follow-up.     

Radioimmunotherapy for non-Hodgkin lymphoma: historical development and current status

Radioimmunotherapy treatment for lymphoma is a novel targeted therapeutic approach. Several years of development of radioimmunotherapeutic compounds came to fruition in February of 2002 when 90Y-ibritumomab tiuxetan (Zevalin, Y2B8) was approved in the USA and later in Europe, for the treatment of relapsed or refractory, low grade or transformed B-cell lymphoma in the USA. 90Y-ibritumomab tiuxetan utilizes a monoclonal anti-CD20 antibody to deliver beta-emitting yttrium-90 to the malignant B-cells. Clinical trials have demonstrated its efficacy, with observed clinical responses in the 80 % range. This product has become available in Europe, with simplified administration, for the treatment of relapsed follicular lymphoma. A similar anti-CD20 radiotherapeutic compound, 131I-tositumomab, was subsequently approved in the USA. Promising studies exploring expanded applications of radioimmunotherapy as consolidation, as part of transplant, or in other histologic types have been recently completed or are under way. Radioimmunotherapy has been shown to be an effective and clinically relevant complementary therapeutic approach for patients with lymphoma, bringing the Nuclear Medicine into lymphoma therapeutics.