Robak Tadeusz
Department of Hematology, Medical University of Lodz and Copernicus Memorial Hospital, 93-510 Lodz, ul. Ciołkowskiego 2, Poland.
Curr Cancer Drug Targets. 2008 Mar;8(2):156-71. doi: 10.2174/156800908783769319.
For many years, alkylating agents and purine nucleoside analogs (PNA) have been considered the drug of choice for treatment of chronic lymphocytic leukemia (CLL). More recently the introduction of monoclonal antibodies (mAb), especially rituximab directed against CD20 and alemtuzumab directed against CD52, has renewed interest in CLL therapy. Over the last few years, several new mAbs directed against lymphoid cells have been developed and investigated in preclinical studies and clinical trials. Some of them are highly active in CLL. New mAbs directed against CD20 include human mAb ofatumumab (HuMax CD20), IMMU-106 (hA20) which has a >90% humanized framework and GA-101, a novel third - generation fully humanized and optimized mAb. These agents are highly cytotoxic against B-cell lymphoid cells and are evaluated in CLL. Lumiliximab (anti-CD23 mAb) is a genetically engineered macaque-human immunoglobulin (Ig) A1. This antibody showed high activity and good tolerability in phase I clinical trial and is evaluated in phase I/II clinical trials as a single agent and in combination. Epratuzumab is a humanized anti-CD22 mAb currently used in clinical trials for treatment of non-Hodgkin lymphoma and autoimmune disorders. Further studies are needed to elucidate the role of this agent in CLL. Apolizumab (HU1D10) is a humanized IgG1 antibody specific for a polymorphic determinant found on the HLA-DRbeta chain. Preclinical and early clinical studies suggest that this mAb has some activity in CLL. HCD122 (CHIR-12.12) and SGN-40 are anti-CD40 mAbs which induce cytotoxicity against CLL cells. Phase I study has shown a favorable safety profile and some activity of HCD122 in pretreated CLL patients. Immunotoxins, especially BL22, LMP-2 and denileukin diftitox, are also being evaluated in lymphoid malignancies and seem to be active in CLL. Finally, antiangiogenic mAbs, especially bevacimzumab, have a potential therapeutic role in this disease. In this review, new mAbs, potentially useful in CLL are presented.
多年来，烷化剂和嘌呤核苷类似物（PNA）一直被视为治疗慢性淋巴细胞白血病（CLL）的首选药物。最近，单克隆抗体（mAb）的引入，尤其是针对CD20的利妥昔单抗和针对CD52的阿仑单抗，重新引发了人们对CLL治疗的兴趣。在过去几年中，几种针对淋巴细胞的新型单克隆抗体已被研发出来，并在临床前研究和临床试验中进行了研究。其中一些在CLL中具有高度活性。针对CD20的新型单克隆抗体包括人源化奥法木单抗（HuMax CD20）、IMMU-106（hA20，其具有>90%的人源化框架）以及GA-101，一种新型的第三代全人源化且经过优化的单克隆抗体。这些药物对B细胞淋巴细胞具有高度细胞毒性，并正在CLL中进行评估。鲁米利单抗（抗CD23单克隆抗体）是一种基因工程改造的猕猴-人免疫球蛋白（Ig）A1。该抗体在I期临床试验中显示出高活性和良好的耐受性，目前正在I/II期临床试验中作为单一药物及联合用药进行评估。依帕珠单抗是一种人源化抗CD22单克隆抗体，目前用于非霍奇金淋巴瘤和自身免疫性疾病治疗的临床试验。需要进一步研究以阐明该药物在CLL中的作用。阿波利单抗（HU1D10）是一种人源化IgG1抗体，对在HLA-DRβ链上发现的多态性决定簇具有特异性。临床前和早期临床研究表明，该单克隆抗体在CLL中具有一定活性。HCD122（CHIR-12.12）和SGN-40是抗CD40单克隆抗体，可诱导对CLL细胞的细胞毒性。I期研究表明，HCD122在预处理的CLL患者中具有良好的安全性和一定活性。免疫毒素，尤其是BL22、LMP-2和地尼白介素-毒素，也正在淋巴细胞恶性肿瘤中进行评估，并且似乎在CLL中具有活性。最后，抗血管生成单克隆抗体，尤其是贝伐单抗，在该疾病中具有潜在的治疗作用。在本综述中，介绍了可能对CLL有用的新型单克隆抗体。
