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(Journal Article) |
JCI insight 1 (9): e87607 (2016)
PRL3-zumab, a first-in-class humanized antibody for cancer therapy.
Min Thura
,
Abdul Qader Omer Al-Aidaroos
,
Wei Peng Yong
,
Koji Kono
,
Abhishek Gupta
,
You Bin Lin
,
Kousaku Mimura
,
Jean Paul Thiery
,
Boon Cher Goh
,
Patrick Tan
,
Ross Soo
,
Cheng William Hong
,
Lingzhi Wang
,
Suling Joyce Lin
,
Elya Chen
,
Sun Young Rha
,
Hyun Cheol Chung
,
Jie Li
,
Sayantani Nandi
,
Hiu Fung Yuen
,
Shu-Dong Zhang
,
Yeoh Khay Guan
,
Jimmy So
,
Qi Zeng
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 elevated PRL-3 mRNA 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.