3A4, a new potential target for B and myeloid lineage leukemias
3A4, a new potential target for B and myeloid lineage leukemias
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3A4，B 型和髓系白血病的新潜在靶点
DOI：
10.3109/1061186x.2011.572973
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发表时间：
2011-11-01
影响因子：
4.5
通讯作者：
Shen, Hongqiang
中科院分区：
文献类型：
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作者：
Li, Sisi;Tang, Yongmin;Shen, Hongqiang
抗体靶向治疗引起了血液科和肿瘤科医生的极大兴趣。已经研究了许多抗体的潜在靶向造血系统恶性肿瘤。其中一些已被证明对这些疾病的患者非常有效。然而，临床上需要更多的抗体。CD45及其亚型可能在靶向治疗方面具有临床潜力。浙江省儿童医院（ZCH）-6 - 3A4（3A4）是一种能够识别CD45亚型的新型抗体，已发现其与造血系统中的限制性细胞成分反应，这可能具有靶向治疗的潜力。在此，我们使用各种细胞和免疫细胞学方法对我们新制备的抗体3A4进行了体外研究。结果表明，抗CD45RA抗体3A4（鼠源IgG1 κ）是一个新克隆。它可以阻断与标准抗CD45RA抗体（克隆名L48）识别的CD45RA表位的结合。3A4对患者新鲜白血病细胞和明确定义的白血病细胞系的反应性与L48的反应性基本相似，但前者识别的白血病细胞比后者多。木瓜蛋白酶处理后的细胞计数分析显示，在37 ℃孵育4 h后，3A4抗体对靶细胞的内化率高达71.3%，显著高于L48的内化率（20.4%）。采用活性酯法制备去甲斑蝥素（NCTD）结合的免疫毒素（NCTD-3A4）。96 h后，对KG1a的靶向抑制率高达61.10%，与3A4阴性Nalm-6细胞的靶向抑制率（3.56%，P <0.01）相比，差异有统计学意义。结论：抗CD45RA抗体3A4可能是一种新的白血病靶分子，对造血系统恶性肿瘤具有靶向治疗潜力，值得进一步开发。
Antibody-targeting therapy has drawn great interests to the hematologists and oncologists. Many antibodies have been studied for their potential targeting for hematopoietic malignancies. A few have been proved to be very effective for patients with these diseases. However, more antibodies are needed for clinical use. CD45 and its isoforms may convey clinical potential in terms of targeting therapy. Zhejiang Children's Hospital (ZCH)-6-3A4 (3A4), a novel antibody that can recognize an isoform of CD45 has been found to react with restricted cell components in hematopoietic system, which may have the potential for targeting therapy. Herein, we conducted an in vitro study of our newly prepared antibody 3A4 using various cellular and immunocytological methods. The results showed that the antibody 3A4 (murine IgG1 kappa) was a new clone of anti-CD45RA. It could block the binding to an epitope of CD45RA recognized by a standard anti-CD45RA antibody (Clone name L48). The reactivity of the 3A4 to both fresh leukemia cells from patients and well-defined leukemia cell lines was largely similar to those of L48, but the former recognized more leukemia cells than the latter. Cytometric analysis after papain treatment showed that the internalization rate of the 3A4 antibody to the target cells was as high as 71.3% after incubation at 37 degrees C for 4 h, which was significantly higher than that of L48 (20.4%). The norcantharidin (NCTD)-conjugated immunotoxin (NCTD-3A4) was generated using an active ester method. The targeting inhibition rate on KG1a was as high as 61.10% after 96 h incubation in a dose-dependent manner, which was significantly higher than that (3.56%, P < 0.01) with 3A4-negative Nalm-6 cells. In conclusion, our new anti-CD45RA antibody 3A4 is probably a new target molecule of leukemia cells and holds a targeting therapeutic potential for hematopoietic malignancies, which warrants further development of this agent.