Characterization and evaluation of the antitumour activity of a dual-targeting monoclonal antibody against claudin-3 and claudin-4.
BACKGROUND
Because human claudin-3 and claudin-4 (CLDN3 and CLDN4) are overexpressed in a variety of carcinomas, they are promising targets for cancer therapy. The aim of the present study was to generate a dual-targeting monoclonal antibody against CLDN3 and CLDN4 and evaluate its antitumour activity.


METHODS
BALB/c mice were immunised with CLDN4-expressing Chinese hamster ovary cells and cell-based screening was performed. The antibody-binding epitope of CLDN3 and CLDN4 and the antitumour activity of the antibody were evaluated.


RESULTS
A monoclonal antibody, KM3907 (IgG2a), which recognised CLDN3 and CLDN4, but not CLDN5, CLDN6 and CLDN9, was successfully isolated. The binding assay of KM3907 revealed that KM3907 recognised the extracellular loop 1 of CLDN3 and CLDN4. Mouse human chimeric IgG1 induced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in vitro, and treatment with murine KM3907 significantly inhibited tumour formation in SCID mice in vivo.


CONCLUSIONS
A dual-targeting monoclonal antibody against CLDN3 and CLDN4 is a promising strategy for cancer immunotherapy.
Antibody Research Laboratories, Kyowa Hakko Kirin Co Ltd, Tokyo, Japan.
Mariko
M
Kato-Nakano
Masayo
M
Suzuki
Shinobu
S
Kawamoto
Akiko
A
Furuya
So
S
Ohta
Kazuyasu
K
Nakamura
Hiroshi
H
Ando
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016466:CHO Cells; D002460:Cell Line; D049109:Cell Proliferation; D062465:Claudin-3; D062506:Claudin-4; D006224:Cricetinae; D003412:Cricetulus; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D017386:Sequence Homology, Amino Acid; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; C568122:CLDN3 protein, human; C568157:CLDN4 protein, human; D062465:Claudin-3; D062506:Claudin-4; C568123:Cldn3 protein, mouse; C568158:Cldn4 protein, mouse; D008565:Membrane Proteins