title: PRL3-zumab, a first-in-class humanized antibody for cancer therapy.
abstract: Novel, tumor-specific drugs are urgently needed for a breakthrough in cancer therapy. Herein, we generated a first-in-class humanized antibody (PRL3-zumab) against PRL-3, an intracellular tumor-associated phosphatase upregulated in multiple human cancers, for unconventional cancer immunotherapies. We focused on gastric cancer (GC), wherein elevatedPRL-3mRNA levels significantly correlated with shortened overall survival of GC patients. PRL-3 protein was overexpressed in 85% of fresh-frozen clinical gastric tumor samples examined but not in patient-matched normal gastric tissues. Using human GC cell lines, we demonstrated that PRL3-zumab specifically blocked PRL-3+, but not PRL-3-, orthotopic gastric tumors. In this setting, PRL3-zumab had better therapeutic efficacy as a monotherapy, rather than simultaneous combination with 5-fluorouracil or 5-fluorouracil alone. PRL3-zumab could also prevent PRL-3+tumor recurrence. Mechanistically, we found that intracellular PRL-3 antigens could be externalized to become "extracellular oncotargets" that serve as bait for PRL3-zumab binding to potentially bridge and recruit immunocytes into tumor microenvironments for killing effects on cancer cells. In summary, our results document a comprehensive cancer therapeutic approach to specific antibody-targeted therapy against the PRL-3 oncotarget as a case study for developing antibodies against other intracellular targets in drug discovery.
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Min
authors.initials: M
authors.lastname: Thura
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Abdul Qader Omer
authors.initials: AQO
authors.lastname: Al-Aidaroos
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Wei Peng
authors.initials: WP
authors.lastname: Yong
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Division of General Surgery (Upper Gastrointestinal Surgery), National University Hospital, Singapore.
authors.forename: Koji
authors.initials: K
authors.lastname: Kono
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: You Bin
authors.initials: YB
authors.lastname: Lin
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Kousaku
authors.initials: K
authors.lastname: Mimura
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Thiery
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Boon Cher
authors.initials: BC
authors.lastname: Goh
authors.affiliation: Genome Institute of Singapore, A*STAR, Singapore.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Ross
authors.initials: R
authors.lastname: Soo
authors.affiliation: Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, USA.
authors.forename: Cheng William
authors.initials: CW
authors.lastname: Hong
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Lingzhi
authors.initials: L
authors.lastname: Wang
authors.affiliation: Genome Institute of Singapore, A*STAR, Singapore.
authors.forename: Suling Joyce
authors.initials: SJ
authors.lastname: Lin
authors.affiliation: Division of General Surgery (Upper Gastrointestinal Surgery), National University Hospital, Singapore.
authors.forename: Elya
authors.initials: E
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, Yonsei Cancer Research Institute, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Rha
authors.affiliation: Department of Internal Medicine, Yonsei Cancer Research Institute, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Hyun Cheol
authors.initials: HC
authors.lastname: Chung
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Sayantani
authors.initials: S
authors.lastname: Nandi
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Hiu Fung
authors.initials: HF
authors.lastname: Yuen
authors.affiliation: Northern Ireland Centre for Stratified Medicine, Ulster University, C-TRIC, Londonderry, United Kingdom.
authors.forename: Shu-Dong
authors.initials: SD
authors.lastname: Zhang
authors.affiliation: Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Yeoh Khay
authors.initials: YK
authors.lastname: Guan
authors.affiliation: Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Division of Surgical Oncology (Upper Gastrointestinal Surgery), National University Cancer Institute, Singapore.
authors.forename: Jimmy
authors.initials: J
authors.lastname: So
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zeng
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000276:immunology*; D009364:Neoplasm Recurrence, Local; D017027:Protein Tyrosine Phosphatases / Q000276:immunology*; D013274:Stomach Neoplasms / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D009363:Neoplasm Proteins; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases