TY - JOUR
T1 - HMMC-1
T2 - A humanized monoclonal antibody with therapeutic potential against müllerian duct-related carcinomas
AU - Nozawa, Shiro
AU - Aoki, Daisuke
AU - Tsukazaki, Katsumi
AU - Susumu, Nobuyuki
AU - Sakayori, Motoko
AU - Suzuki, Nao
AU - Suzuki, Atsushi
AU - Wakita, Rie
AU - Mukai, Makio
AU - Egami, Yuko
AU - Kojima-Aikawa, Kyoko
AU - Ishida, Isao
AU - Belot, Frederic
AU - Hindsgaul, Ole
AU - Fukuda, Minoru
AU - Fukuda, Michiko N.
PY - 2004/10/15
Y1 - 2004/10/15
N2 - 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 by in vitro cytotoxicity 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 1 O-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 novel O-glycan structure. The unique specificity and cytotoxicity of HMMC-1 strongly suggest a therapeutic potential of this antibody.
AB - 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 by in vitro cytotoxicity 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 1 O-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 novel O-glycan structure. The unique specificity and cytotoxicity of HMMC-1 strongly suggest a therapeutic potential of this antibody.
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U2 - 10.1158/1078-0432.CCR-04-0802
DO - 10.1158/1078-0432.CCR-04-0802
M3 - Article
C2 - 15501987
AN - SCOPUS:6044234744
SN - 1078-0432
VL - 10
SP - 7071
EP - 7078
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 20
ER -
