放射免疫治疗中载体的研究进展

放射免疫治疗是应用肿瘤细胞表面表达的特异性分子的单克隆抗体进行核素靶向治疗的一种新方法。通过改进放射性核素的载体,放射免疫治疗的技术不断发展、成熟,其应用范围不断扩展,在未来的疾病定位诊断及治疗中具有很高的应用价值。     

90Y在肿瘤治疗中的应用

成功的肿瘤治疗应在减慢肿瘤生长和扩散的同时，较少或不损伤正常组织。９０Ｙ作为一种治疗肿瘤的放射性核素，通过标记单克隆抗体、玻璃微球等多种途径，在肿瘤的放射免疫治疗、肝癌的动脉栓塞治疗及瘤内直接注入放射性核素等治疗方法中得到了广泛的应用     

用于放免治疗的核素研究进展

放射免疫治疗肿瘤具有独特优势，许多新的核素被用于制备肿瘤放免治疗药物。高能α、β粒子及抗肿瘤导向载体的应用促进了放免治疗药物的发展。本文介绍了用于放射免疫治疗的核素最新研究进展，归纳了用于放射免治疗的常用放射性核素，并比较了各自的优缺点，指出了放射性核素用于放射免疫治疗过程中存在的问题、可能的解决方法及今后的发展趋势。     

用于放免治疗的核素研究进展

放射免疫治疗肿瘤具有独特优势,许多新的核素被用于制备肿瘤放免治疗药物.高能α、β粒子及抗肿瘤导向载体的应用促进了放免治疗药物的发展.本文介绍了用于放射免疫治疗的核素最新研究进展,归纳了用于放射免治疗的常用放射性核素,并比较了各自的优缺点,指出了放射性核素用于放射免疫治疗过程中存在的问题、可能的解决方法及今后的发展趋势.     

肿瘤核素靶向治疗的研究进展

对近年来肿瘤核素靶向治疗的现状及进展进行了论述,包括放射免疫治疗、受体介导的靶向治疗、基因靶向治疗及化疗药物联合核素治疗四个大类,侧重介绍了这些治疗方法的常用标记载体的应用研究。同时,突出介绍了吲哚美辛的最新研究进展,并展望该药与核素靶向治疗联合应用的潜在研究价值。     

肿瘤核素靶向治疗新进展

利用靶向分子将放射性核素定向导入肿瘤组织实现核素靶向治疗是肿瘤治疗的重要方法。利用单克隆抗体或小分子肽携带治疗性放射性核素,分别与肿瘤细胞表面表达丰富的抗原或受体特异性结合而开展放射免疫治疗或受体介导的核素治疗是靶向治疗的主要策略。近年来,这两种靶向治疗取得较大进展,部分已进入临床应用。随着靶向分子的不断出现、分子靶向技术的不断完善,肿瘤核素靶向治疗终将成为肿瘤治疗的重要方法。     

放射免疫治疗的若干进展

经过数十年的研发与改进，放射性核素标记的单克隆抗体（简称单抗）已经用于临床，开辟了一种治疗癌症的新方法——放射免疫治疗（radioimmunotherapy，RIT）。     

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)患者进行放射免疫治疗取得了长足的发展。     

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。     

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.     

Development of radioimmunotherapeutic and diagnostic antibodies: an inside-out view

Only a handful of radiolabeled antibodies (Abs) have gained US Food and Drug Administration (FDA) approval for use in clinical oncology, including four immunodiagnostic agents and two targeted radioimmunotherapeutic agents. Despite the advent of nonimmunogenic Abs and the availability of a diverse library of radionuclides, progress beyond early Phase II radioimmunotherapy (RIT) studies in solid tumors has been marginal. Furthermore, [¹⁸F]fluorodeoxyglucose continues to dominate the molecular imaging domain, underscored by a decade-long absence of any newly approved Ab-based imaging agent (none since 1996). Why has the development of clinically successful Abs for RIT been limited to lymphoma? What obstacles must be overcome to allow the FDA approval of immuno-positron emission tomography (immuno-PET) imaging agents? How can we address the unique challenges that have thus far prevented the introduction of Ab-based imaging agents and therapeutics for solid tumors? Many poor decisions have been made regarding radiolabeled Abs, but useful insight can be gained from these mistakes. The following review addresses the physical, chemical, biological, clinical, regulatory and financial limitations that impede the progress of this increasingly important class of drugs.     

Comparison of immunoscintigraphy, efficacy, and toxicity of conventional and pretargeted radioimmunotherapy in CD20-expressing human lymphoma xenografts.

Pretargeted radioimmunotherapy (RIT) using streptavidin (sAv)-conjugated antibodies before radiolabeled-biotin is a promising approach to improve absorbed dose ratios and achieve high durable remission rates with diminished systemic toxicity. This study compared the immunoscintigraphy, toxicity, and therapeutic efficacy of pretargeted RIT with conventional RIT using an anti-CD20 antibody. METHODS: Athymic mice bearing Ramos human Burkitt's lymphoma xenografts were injected intraperitoneally with a 1F5-sAv conjugate followed 24 h later by a galactosylated, biotinylated clearing agent (CA) and, finally, 3 h later by (111)In- or (90)Y-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin. The comparison groups consisted of mice injected with conventional, directly labeled (111)In- or (90)Y-1F5. RESULTS: Rapid tumor uptake of radioactivity within 2 h was observed with the pretargeting approach, resulting in high-contrast tumor images at 24 h with minimal blood-pool radioactivity. Although conventional radiolabeled antibodies produced clear tumor images at 24 h, a large amount of radioactivity was present in the blood pool. The tumor-to-blood ratio was 3.5:1 with pretargeting compared with 0.4:1 with conventional (111)In-1F5. Pretargeted RIT with 29.6 MBq (800 micro Ci) (90)Y-DOTA-biotin cured 100% of mice with tolerable toxicity, whereas conventional RIT with (90)Y-1F5 at a dose of 14.8 MBq (400 micro Ci) produced no cures, induced profound pancytopenia, and was lethal to all mice. CONCLUSION: These results suggest that anti-CD20 pretargeted RIT may be superior to conventional radiolabeled antibodies in terms of radioimmunoscintigraphy, toxicity, and therapeutic efficacy for treatment of B-cell lymphomas.     

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.     

Radioimmunoimaging and radioimmunotherapy: will these be routine procedures?

Despite major progress made during the past 25 years in the genetic engineering and labeling of monoclonal antibodies (Mab) and in the understanding of the uptake and kinetics of radiolabeled Mab by normal and tumor tissues, immunoscintigraphy never succeeded in becoming a routine procedure, compared with a bone or gallium scan. The more and more generalized availability of positron emission tomography (PET) with Fluorine-18 fluorodeoxyglucose (FDG) for diagnosis and staging of malignant diseases will probably definitively seal the fate of radioimmunodiagnosis as it has been conceived up until now. With respect to the nonspecificity of deoxyglucose uptake by tumor cells, it is not to be excluded that antibodies, or more likely antibody fragments, labeled with positron emitters might be used for tissue characterization. The recent success of radioimmunotherapy, especially in B-cell malignancies, entitles us to expect that RIT will become part of standard therapy of patients with malignancies. In that case, immunoscintigraphy will be needed for treatment planning (patient selection and dosimetry). One might even speculate that the oncologists who are becoming familiar with nuclear medicine tracer techniques for pretreatment evaluation might be interested in extending them to distribution and kinetic studies of other cytotoxic drugs. The close cooperation between nuclear medicine specialists, oncologists, and hematologists is essential to make radioimmunotherapy a routine procedure.     

Localization of radiolabeled anti-CEA antibody in subcutaneous and intrahepatic colorectal xenografts: influence of tumor size and location within host organ on antibody uptake

IntroductionRadioimmunotherapy (RIT) has been shown to be more effective against solid tumor micrometastases, possibly due to an inverse relationship between tumor size and radiolabeled antibody uptake. In this study, the accretion of radiolabeled antibody in intrahepatic micrometastases in an experimental model was investigated using quantitative digital autoradiography, enabling the analysis of antibody uptake in microscopic tumors.MethodsMice bearing subcutaneous or intrahepatic metastatic models of LS174T colorectal cancer were injected with radiolabeled anti-carcinoembryonic antigen antibody ([¹²⁵I]A5B7). Tissues were taken to investigate distribution of radionuclide and tumor uptake. In a therapy study, mice bearing intrahepatic metastatic tumors were injected with [¹³¹I]A5B7.ResultsSubcutaneous tumors and large metastatic deposits had similar uptake (e.g., ～15%ID/g at 24 h). Small metastatic deposits had higher uptake (e.g., ～80%ID/g at 24 h) and prolonged retention at later time points. Small deposit uptake was significantly reduced by accompanying large deposits in the same liver. RIT resulted in increased survival time (untreated mean survival of 21.6±12.9 vs. treated mean survival of 39.1±30.8 days), but there was a large range of response within groups, presumably due to variation in pattern and extent of tumor as observed in the biodistribution study. Liver function tests and body weight did not change with tumor growth or therapy response, strongly supporting the use of in vivo imaging in metastatic tumor therapy studies.ConclusionsRadioimmunodetection and therapy might be greatly influenced by the size and distribution of intrahepatic tumor deposits.     

Melanoma stem cells in experimental melanoma are killed by radioimmunotherapy

IntroductionIn spite of recently approved B-RAF inhibitors and immunomodulating antibodies, metastatic melanoma has poor prognosis and novel treatments are needed. Melanoma stem cells (MSC) have been implicated in the resistance of this tumor to chemotherapy. Recently we demonstrated in a Phase I clinical trial in patients with metastatic melanoma that radioimmunotherapy (RIT) with 188-Rhenium(¹⁸⁸Re)-6D2 antibody to melanin was a safe and effective modality. Here we investigated the interaction of MSC with RIT as a possible mechanism for RIT efficacy.MethodsMice bearing A2058 melanoma xenografts were treated with either 1.5 mCi ¹⁸⁸Re-6D2 antibody, saline, unlabeled 6D2 antibody or ¹⁸⁸Re-labeled non-specific IgM.ResultsOn Day 28 post-treatment the tumor size in the RIT group was 4-times less than in controls (P < 0.001). The tumors were analyzed by immunohistochemistry and FACS for two MSC markers — chemoresistance mediator ABCB5 and H3K4 demethylase JARID1B. There were no significant differences between RIT and control groups in percentage of ABCB5 or JARID1B-positive cells in the tumor population. Our results demonstrate that unlike chemotherapy, which kills tumor cells but leaves behind MSC leading to recurrence, RIT kills MSC at the same rate as the rest of tumor cells.ConclusionsThese results have two main implications for melanoma treatment and possibly other cancers. First, the susceptibility of ABCB5 + and JARID1B + cells to RIT in melanoma might be indicative of their susceptibility to antibody-targeted radiation in other cancers where they are present as well. Second, specifically targeting cancer stem cells with radiolabeled antibodies to ABCB5 or JARID1B might help to completely eradicate cancer stem cells in various cancers.     

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.     

Radioimmunotherapy of B-cell non-Hodgkin's lymphoma.

In the past decade, several new antibody-based therapies - using either radiolabelled or unlabelled monoclonal antibodies - have become available for the treatment of patients with refractory or recurrent non-Hodgkin's lymphoma (NHL). Unlabelled monoclonal antibodies (mAbs) kill lymphoma cells by activating host immune effector mechanisms, or by inducing apoptosis. These mAbs can also be used to guide radionuclides to the lymphoma. This radioimmunotherapy (RIT) has been studied with various nuclides (131I, 90Y, 67Cu and 186Re) and with various mAbs. In this review the radionuclides, methods of dosing and recent RIT studies in patients with B-cell NHL are reviewed. Most of these studies demonstrate that RIT is an effective new treatment modality for NHL.     

Protein targeting constructs in alpha therapy

The progress in the field of targeted α-particle therapy (TAT) has to a great extent been enhanced by developments in both recombinant DNA technology and radionuclide labeling chemistry. Advances in genomics and proteomics have promoted an increase in the identification of novel targets and molecules that can define different diseases, such as cancer. In radioimmunotherapy (RIT), the primary goal is to improve delivery to and therapeutic efficacy of the cancer cells, whilst minimizing toxicity. Different approaches have been investigated to achieve this, such as reducing the size of the carrier, pretargeting, multidosing, locoregional administration and using a cocktail of radiolabeled monoclonal antibodies for targeting multiple antigens simultaneously. Some of these approaches have been encouraging, but translation of TAT into the clinic has been slow, in part because of the limited availability and the short physical half-lives of some of the available α-particle emitters. The clinical studies carried out to date have been promising, although many challenges remain in order to make TAT safe and economically feasible. In this paper a number of different targeting constructs used hitherto that may be promising carriers for TAT in the future are presented and discussed. The constructs include enzymatic cleaved antibody fragments (Fab and F(ab˙)2 fragments); genetically engineered antibody fragments (scFv monomer, dimer (i.e. diabody) and tetramer, CH2 domain deleted antibody fragments); other protein targeting constructs such as affibodies and peptides as well as liposomal delivery.     

High pre-therapy [99mTc]pertechnetate thyroid uptake, thyroid size and thyrostatic drugs: predictive factors of failure in [131I]iodide therapy in Graves' disease

BACKGROUND AND OBJECTIVE: Several factors may interfere with the success rate of radioiodine therapy (RIT) in Graves' disease. Our aim was to evaluate, retrospectively, some of these factors in the outcome of RIT. METHODS: Patient gender, age at diagnosis, ophthalmopathy, disease duration, thyroid size, drug used as clinical treatment, thionamide withdrawal period during RIT preparation, FT4, TSH and [99mTc]pertechnetate thyroid uptake prior to RIT were studied as potential interference factors for RIT success. Eighty-two Graves' disease patients were submitted to RIT after thionamide treatment failure. Prior to RIT, 67 patients were receiving methimazole and 15 propylthiouracil. Thirty-three patients received thionamides during RIT; in 49 patients the medication was withdrawn for 2-30 days. [99mTc]pertechnetate thyroid uptake was determined before RIT. Fixed doses of 370 MBq of [131I]iodide were administered to all patients. RESULTS: Eleven patients became euthyroid; 40 became hypothyroid and 31 remained hyperthyroid. There was no association between outcome and age at diagnosis, gender, ophthalmopathy, pre-RIT FT4, TSH, antithyroid antibodies or thyrostatic drug. Multiple logistic regression showed higher probability of treatment success in patients with thyroid mass <53 g (odds ratio (OR)=8.9), with pre-RIT thyroid uptake <12.5% (OR=4.1) and in patients who withdrew thionamide before RIT (OR=4.9). CONCLUSIONS: Fixed doses of 370 MBq of radioiodine seem to be practical and effective for treating Graves' disease patients with [99mTc]pertechnetate uptake <12.5% and thyroid mass <53 g. This treatment is clearly not recommended for patients with large goitre. In contrast to what could be expected, patients with a high pre-RIT thyroid uptake presented a higher rate of RIT failure.