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首页> 外文期刊>Clinical cancer research: an official journal of the American Association for Cancer Research >Antibody-drug conjugates of calicheamicin derivative: gemtuzumab ozogamicin and inotuzumab ozogamicin.
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Antibody-drug conjugates of calicheamicin derivative: gemtuzumab ozogamicin and inotuzumab ozogamicin.

机译：加利车霉素衍生物的抗体-药物偶联物：吉妥单抗ozogamicin和inotuzumab ozogamicin。

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Antibody-drug conjugates (ADC) are an attractive approach for the treatment of acute myeloid leukemia and non-Hodgkin lymphomas, which in most cases, are inherently sensitive to cytotoxic agents. CD33 and CD22 are specific markers of myeloid leukemias and B-cell malignancies, respectively. These endocytic receptors are ideal for an ADC strategy because they can effectively carry the cytotoxic payload into the cell. Gemtuzumab ozogamicin (GO, Mylotarg) and inotuzumab ozogamicin consist of a derivative of calicheamicin (a potent DNA-binding cytotoxic antibiotic) linked to a humanized monoclonal IgG4 antibody directed against CD33 or CD22, respectively. Both of these ADCs have a target-mediated pharmacokinetic disposition. GO was the first drug to prove the ADC concept in the clinic, specifically in phase II studies that included substantial proportions of older patients with relapsed acute myeloid leukemia. In contrast, in phase III studies, it has thus far failed to show clinical benefit in first-line treatment in combination with standard chemotherapy. Inotuzumab ozogamicin has shown remarkable clinical activity in relapsed/refractory B-cell non-Hodgkin lymphoma, and it has started phase III evaluation. The safety profile of these ADCs includes reversible myelosuppression (especially neutropenia and thrombocytopenia), elevated hepatic transaminases, and hyperbilirubinemia. There have been postmarketing reports of hepatotoxicity, especially veno-occlusive disease, associated with GO. The incidence is ~2%, but patients who undergo hematopoietic stem cell transplantation have an increased risk. As we steadily move toward the goal of personalized medicine, these kinds of agents will provide a unique opportunity to treat selected patient subpopulations based on the expression of their specific tumor targets.
机译：抗体-药物偶联物（ADC）是治疗急性髓细胞性白血病和非霍奇金淋巴瘤的一种有吸引力的方法，在大多数情况下，它们对细胞毒性剂具有内在敏感性。 CD33和CD22分别是髓样白血病和B细胞恶性肿瘤的特异性标志物。这些内吞受体是ADC策略的理想选择，因为它们可以有效地将细胞毒性有效载荷带入细胞。 Gemtuzumab ozogamicin（GO，Mylotarg）和inotuzumab ozogamicin由加利车霉素的衍生物（一种有效的DNA结合细胞毒性抗生素）组成，分别与针对CD33或CD22的人源化单克隆IgG4抗体连接。这两个ADC均具有靶标介导的药代动力学特征。 GO是首款在临床上证明ADC概念的药物，特别是在II期研究中，该研究包括了相当一部分老年复发性急性髓细胞白血病患者。相比之下，在III期研究中，到目前为止，在一线治疗与标准化疗联合使用中，尚无临床疗效。依托珠单抗ozogamicin在复发/难治性B细胞非霍奇金淋巴瘤中已显示出显着的临床活性，并已开始III期评估。这些ADC的安全性包括可逆性骨髓抑制（尤其是中性粒细胞减少和血小板减少），肝转氨酶升高和高胆红素血症。上市后已有关于GO引起的肝毒性，尤其是静脉闭塞性疾病的报道。发生率约为2％，但是进行造血干细胞移植的患者风险增加。随着我们稳步朝着个性化医学的目标迈进，这些药物将为基于特定肿瘤靶标表达的选定患者亚群提供独特的机会。

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