title: Anti-tumor effect against human cancer xenografts by a fully human monoclonal antibody to a variant 8-epitope of CD44R1 expressed on cancer stem cells.
abstract: BACKGROUND
  CD44 is a major cellular receptor for hyaluronic acids. The stem structure of CD44 encoded by ten normal exons can be enlarged by ten variant exons (v1-v10) by alternative splicing. We have succeeded in preparing MV5 fully human IgM and its class-switched GV5 IgG monoclonal antibody (mAb) recognizing the extracellular domain of a CD44R1 isoform that contains the inserted region coded by variant (v8, v9 and v10) exons and is expressed on the surface of various human epithelial cancer cells.
  
  
  RESULTS
  We demonstrated the growth inhibition of human cancer xenografts by a GV5 IgG mAb reshaped from an MV5 IgM. The epitope recognized by MV5 and GV5 was identified to a v8-coding region by the analysis of mAb binding to various recombinant CD44 proteins by enzyme-linked immunosorbent assay. GV5 showed preferential reactivity against various malignant human cells versus normal human cells assessed by flow cytometry and immunohistological analysis. When ME180 human uterine cervix carcinoma cells were subcutaneously inoculated to athymic mice with GV5, significant inhibition of tumor formation was observed. Furthermore, intraperitoneal injections of GV5markedly inhibited the growth of visible established tumors from HSC-3 human larynx carcinoma cells that had been subcutaneously transplanted one week before the first treatment with GV5. From in vitro experiments, antibody-dependent cellular cytotoxicity and internalization of CD44R1 seemed to be possible mechanisms for in vivo anti-tumor activity by GV5.
  
  
  CONCLUSIONS
  CD44R1 is an excellent molecular target for mAb therapy of cancer, possibly superior to molecules targeted by existing therapeutic mAb, such as Trastuzumab and Cetuximab recognizing human epidermal growth factor receptor family.
authors.affiliation: Cell Biology Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, Kinki University, Higashiosaka-shi, Osaka, Japan.
authors.forename: Kazue
authors.initials: K
authors.lastname: Masuko
authors.forename: Shogo
authors.initials: S
authors.lastname: Okazaki
authors.forename: Mayumi
authors.initials: M
authors.lastname: Satoh
authors.forename: Goh
authors.initials: G
authors.lastname: Tanaka
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ikeda
authors.forename: Ryota
authors.initials: R
authors.lastname: Torii
authors.forename: Eri
authors.initials: E
authors.lastname: Ueda
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakano
authors.forename: Masaaki
authors.initials: M
authors.lastname: Danbayashi
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Tsuruoka
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Ohno
authors.forename: Hideki
authors.initials: H
authors.lastname: Yagi
authors.forename: Noritsugu
authors.initials: N
authors.lastname: Yabe
authors.forename: Hideaki
authors.initials: H
authors.lastname: Yoshida
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Tahara
authors.forename: Shiro
authors.initials: S
authors.lastname: Kataoka
authors.forename: Taichi
authors.initials: T
authors.lastname: Oshino
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shindo
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Niwa
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Ishimoto
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.forename: Takashi
authors.initials: T
authors.lastname: Masuko
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000918:Antibody Specificity / Q000276:immunology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000939:Epitopes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D014644:Genetic Variation; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007150:Immunohistochemistry; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000939:Epitopes; D018960:Hyaluronan Receptors; D020033:Protein Isoforms