HMMC-1: a humanized monoclonal antibody with therapeutic potential against Mullerian duct-related carcinomas.
HMMC-1: a humanized monoclonal antibody with therapeutic potential against Mullerian duct-related carcinomas.
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HMMC-1：一种人源化单克隆抗体，具有治疗苗勒氏管相关癌的潜力。
DOI：
10.1158/1078-0432.ccr-04-0802
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Fukuda,Michik
中科院分区：
文献类型：
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作者：
Nozawa,Shiro;Aoki,Daisuke;Tsukazaki,Katsumi;Susumu,Nobuyuki;Sakayori,Motoko;Suzuki,Nao;Suzuki,Atsushi;Wakita,Rie;Mukai,Makio;Egami,Yuko;Kojima-Aikawa,Kyoko;Ishida,Isao;Belot,Frederic;Hindsgaul,Ole;Fukuda,Minoru;Fukuda,Michik
目的：本研究的目的是产生一个人的单克隆抗体特异性的妇科cancers. Experimental设计的治疗妇科cancer.Experimental设计：Transchromosomal KM小鼠免疫与人子宫内膜癌细胞系SNG-S。将KM小鼠脾细胞与小鼠骨髓瘤细胞之间构建杂交瘤。用免疫组化法检测抗体对妇科肿瘤病理标本的反应性。体外细胞毒实验检测HMMC-1对SNG-S细胞的细胞毒作用。结果：HMMC-1是一种人源性IgM单克隆抗体，对子宫内膜腺癌、宫颈腺癌和卵巢上皮癌的阳性率分别为54.6%、76.9%和75.0%。HMMC-1不与处于增殖或分泌期的正常子宫内膜、正常子宫颈或来自其他器官的正常和恶性组织反应，而它与胆囊和肾集合管的上皮反应较弱。HMMC-1具有抗原依赖性和补体介导的细胞毒性。在与编码岩藻糖基化延伸核心10-聚糖所需的两种糖基转移酶的cDNA共转染后，哺乳动物细胞表达HMMC-1抗原。最后，合成的Fucα1→2Galβ1→4GlcNAcβ1→ 3Galβ1 →3GalNAcα1-辛基抑制HMMC-1与SNG-S细胞的结合。HMMC-1的独特特异性和细胞毒性强烈表明该抗体的治疗潜力。
Purpose:The purpose of this research was to generate a human monoclonal antibody specific to gynecological cancers and to evaluate such an antibody as therapy for gynecological cancers.Experimental Design:Transchromosomal KM mice were immunized with the human uterine endometrial cancer cell line SNG-S. Hybridomas were constructed between spleen cells from KM mice and mouse myeloma cells. Reactivity of the antibody was evaluated by immunohistochemistry of pathological specimens of gynecological cancers. Cytotoxicity of HMMC-1 against SNG-S cells was tested byin vitrocytotoxicity assays. The epitope of HMMC-1 was determined by transfection with a panel of glycosyltransferase cDNAs and by inhibition assays with chemically synthesized oligosaccharides.Results:HMMC-1 is a human IgM monoclonal antibody that reacts positively with müllerian duct-related carcinomas with positive rates of 54.6% against uterine endometrial adenocarcinoma, 76.9% against uterine cervical adenocarcinoma, and 75.0% against epithelial ovarian cancer. HMMC-1 does not react with normal endometrium at proliferative or secretory phases, normal uterine cervix, or normal and malignant tissue from other organs, whereas it reacts weakly with the epithelium of the gall bladder and the collecting duct of the kidney. HMMC-1 exhibits antigen-dependent and complement-mediated cytotoxicity. Upon cotransfection with cDNAs encoding two glycosyltransferases required for fucosylated extended core 1O-glycan, mammalian cells express HMMC-1 antigen. Finally, binding of HMMC-1 to SNG-S cells is inhibited by synthetic Fucα1→2Galβ1→4GlcNAcβ1→3Galβ1→3GalNAcα1-octyl.Conclusions:These results indicate that HMMC-1 specifically recognizes a novelO-glycan structure. The unique specificity and cytotoxicity of HMMC-1 strongly suggest a therapeutic potential of this antibody.