Molecular cloning and characterization of a surface antigen preferentially overexpressed on multiple myeloma cells
Molecular cloning and characterization of a surface antigen preferentially overexpressed on multiple myeloma cells
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DOI：
10.1006/bbrc.1999.0683
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发表时间：
1999-05-19
影响因子：
3.1
通讯作者：
Tsuchiya, M
中科院分区：
文献类型：
--
作者：
Ohtomo, T;Sugamata, Y;Tsuchiya, M
HM1.24抗原已被鉴定为在终末分化B细胞上优先表达的表面分子，在多发性骨髓瘤细胞中观察到其过表达。因此，HM1.24抗原有望成为基于抗体的多发性骨髓瘤免疫治疗中最有效的靶分子。本研究鉴定了人HM1.24抗原的cDNA，并分析了其基因结构，包括启动子区。HM1.24抗原是一种II型膜糖蛋白，已报道为骨髓基质细胞表面抗原BST2，可能以同型二聚体存在于骨髓瘤细胞表面。虽然在骨髓瘤细胞中过度表达的原因尚不清楚，但非常有趣的是，HM1.24基因的启动子区域具有介导白细胞介素-6 （IL-6）反应基因表达的转录因子STAT3的三个顺式元件的串联重复。由于IL-6是B细胞的分化因子，是多发性骨髓瘤细胞的旁分泌/自分泌生长因子，因此HM1.24抗原的表达可能受STAT3的激活调控。重要的是，人源化抗HM1.24抗体有效地裂解了表达HM1.24抗原与人多发性骨髓瘤细胞一样高的CHO转化子，而不是抗原表达较低的细胞。这一评价表明，ADCC严重依赖于靶抗原的表达水平，因此，针对HM1.24抗原的免疫治疗在临床应用中应该具有很好的潜力。(C) 1999学术出版社。
HM1.24 antigen has been identified as a surface molecule preferentially expressed on terminally differentiated B cells, and its overexpression is observed in multiple myeloma cells. The HM1.24 antigen is, therefore, expected as a most potent target molecule for antibody-based immunotherapy for multiple myeloma. Here, we have identified the cDNA for human HM1.24 antigen and also analyzed its gene structure including the promoter region. The HM1.24 antigen is a type II membrane glycoprotein, which has been reported as a bone marrow stromal cell surface antigen BST2, and may exist as a homodimer on myeloma cell surface. Although a reason for the overexpression in myeloma cells is not understood, very interestingly, the promoter region of the HM1.24 gene has a tandem repeat of three cis elements for a transcription factor, STAT3, which mediates interleukin-6 (IL-6) response gene expression. Since IL-6 is a differentiation factor for B cells, and known as a paracrine/autocrine growth factor for multiple myeloma cells, the expression of HM1.24 antigen may be regulated by the activation of STAT3. Importantly, a humanized anti-HM1.24 antibody effectively lysed the CHO transformants which expressed HM1.24 antigen as high as human multiple myeloma cells, but not the cells with lower antigen expression. This evaluation shows that ADCC heavily depends on the expression level of target antigens and, therefore, the immunotherapy targeting the HM1.24 antigen should have a promising potential in clinical use. (C) 1999 Academic Press.