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.