Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia
Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia
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DOI：
10.1021/bc010021y
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发表时间：
2002-01-01
影响因子：
4.7
通讯作者：
Bernstein, I
中科院分区：
文献类型：
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作者：
Hamann, PR;Hinman, LM;Bernstein, I
CD33在80%的急性髓性白血病（AML）患者中由细胞表达，但在正常造血干细胞中不表达，这表明清除CD33（+）细胞可能在治疗上有益。在人源化抗cd33小鼠抗体P67.6之前，已经选择了一种卡奇霉素肼衍生物的偶联物，通过腙形成连接到抗cd33小鼠抗体P67.6的氧化碳水化合物。然而，cdr接枝的人源化P67.6不能用于碳水化合物缀合物，因为该抗体对高羧酸盐氧化具有意想不到的敏感性。对一系列双功能连接物的探索产生了一类新的钙曲霉素偶联物，称为杂交偶联物，它允许钙曲霉素附着在赖氨酸上，但包含水解释放位点，一个腙，以前被证明是活性所必需的。选择用于临床试验的优化缀合物，gemtuzumab ozogamicin（“gem-ozo”，Mylotarg，以前指定为CMA-676），比它取代的碳水化合物缀合物具有更强的效力和选择性。它对组织培养的HL-60白血病细胞具有选择性细胞毒性，IC50在低至亚pg cal/mL范围内（cal = calicheamicin当量）。给携带HL-60异种移植物的小鼠三次低至50马克卡/公斤的gem-ozo剂量通常会导致长期无肿瘤存活，而非结合的对照偶联物则相对无活性。2 ~ 10 ng cal/mL浓度的Gem-ozo选择性地抑制大量AML患者骨髓细胞形成白血病集落。Gem-ozo在II期试验中也显示出显著的抗AML活性，是FDA批准的第一个抗体靶向化疗药物。
CD33 is expressed by acute myeloid leukemia (AML) cells in >80% of patients but not by normal hematopoietic stem cells, suggesting that elimination of CD33(+) cells may be therapeutically beneficial. A conjugate of a calicheamicin hydrazide derivative attached via hydrazone formation to the oxidized carbohydrates of the anti-CD33 murine antibody P67.6 had been chosen for use in AML prior to humanization of this antibody. However, the CDR-grafted humanized P67.6 could not be used to make the carbohydrate conjugate because of the unexpected sensitivity of this antibody to periodate oxidation. Exploration of a series of bifunctional linkers resulted in a new class of calicheamicin conjugates, termed the hybrid conjugates, that allows for the attachment of the calicheamicin to lysines but incorporates the site of hydrolytic release, a hydrazone, previously shown to be required for activity. The optimized conjugate chosen for clinical trials, gemtuzumab ozogamicin ("gem-ozo", Mylotarg, formerly designated CMA-676), was significantly more potent and selective than the carbohydrate conjugate it replaced. It was selectively cytotoxic to HL-60 leukemia cells in tissue culture with an IC50 in the low to sub-pg cal/mL range (cal = calicheamicin equivalents). Doses of gem-ozo as low as 50 mug cal/kg given three times to mice bearing HL-60 xenografts routinely resulted in long-term, tumor-free survivors, while a nonbinding control conjugate was relatively inactive. Gem-ozo at a concentration of 2 to 10 ng cal/mL selectively inhibited leukemia colony formation by marrow cells from a significant proportion of AML patients. Gem-ozo has also shown significant activity against AML in Phase II trials and is the first antibody-targeted chemotherapeutic agent approved by the FDA.