Development of Human Monoclonal Antibody for Claudin-3 Overexpressing Carcinoma Targeting
Hobin Yang,
Hayeon Park,
Yong Jin Lee,
Jun Young Choi,
TaeEun Kim,
Nirmal Rajasekaran,
Saehyung Lee,
Kyoung Song,
Sungyoul Hong,
Joon-Seok Choi,
Hyunbo Shim,
Young-Deug Kim,
Soohyun Hwang,
Yoon-La Choi,
Young Kee Shin
Affiliations
Hobin Yang
Laboratory of Molecular Pathology and Cancer Genomics, Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 08826, Korea
Hayeon Park
ABION Inc., R&D Center, Seoul 08394, Korea
Yong Jin Lee
ABION Inc., R&D Center, Seoul 08394, Korea
Jun Young Choi
ABION Inc., R&D Center, Seoul 08394, Korea
TaeEun Kim
Laboratory of Molecular Pathology and Cancer Genomics, Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 08826, Korea
Nirmal Rajasekaran
Laboratory of Molecular Pathology and Cancer Genomics, Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 08826, Korea
Saehyung Lee
Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Korea
Kyoung Song
Center for Companion Diagnostics, LOGONE Bio Convergence Research Foundation, Seoul 08826, Korea
Sungyoul Hong
Laboratory of Molecular Pathology and Cancer Genomics, Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 08826, Korea
Joon-Seok Choi
College of Pharmacy Daegu Catholic University Hayang-ro 13-13 Gyeongsan-si, Hayang-eup, Gyeongbuk 38430, Korea
Hyunbo Shim
Department of Life Science, College of Natural Science, Ewha Womans University, Seoul 03760, Korea
Young-Deug Kim
ABION Inc., R&D Center, Seoul 08394, Korea
Soohyun Hwang
Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
Yoon-La Choi
Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
Young Kee Shin
Laboratory of Molecular Pathology and Cancer Genomics, Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 08826, Korea
Most malignant tumors originate from epithelial tissues in which tight junctions mediate cell−cell interactions. Tight junction proteins, especially claudin-3 (CLDN3), are overexpressed in various cancers. Claudin-3 is exposed externally during tumorigenesis making it a potential biomarker and therapeutic target. However, the development of antibodies against specific CLDN proteins is difficult, because CLDNs are four-transmembrane domain proteins with high homology among CLDN family members and species. Here, we developed a human IgG1 monoclonal antibody (h4G3) against CLDN3 through scFv phage display using CLDN3-overexpressing stable cells and CLDN3-embedded lipoparticles as antigens. The h4G3 recognized the native conformation of human and mouse CLDN3 without cross-reactivity to other CLDNs. The binding kinetics of h4G3 demonstrated a sub-nanomolar affinity for CLDN3 expressed on the cell surface. The h4G3 showed antibody-dependent cellular cytotoxicity (ADCC) according to CLDN3 expression levels in various cancer cells by the activation of FcγRIIIa (CD16a). The biodistribution of h4G3 was analyzed by intravenous injection of fluorescence-conjugated h4G3 which showed that it localized to the tumor site in xenograft mice bearing CLDN3-expressing tumors. These results indicate that h4G3 recognizes CLDN3 specifically, suggesting its value for cancer diagnosis, antibody-drug conjugates, and potentially as a chimeric antigen receptor (CAR) for CLDN3-expressing pan-carcinoma.
