Wei Peng Yong, Nicholas Yan Zhi Tan, John Shyi Peng Yuen, Qi Zeng, Min Thura, Iain Beehuat Tan, Su Pin Choo, Lingzhi Wang, Soo-Chin Lee, Matthew C.H. Ng, Jimmy Bok Yan So, Henry Sun Sien Ho, Joanne Ngeow, Abdul Qader Omer Al-aidaroos, Joel Sng, Abhishek Gupta, Yeoh Khay Guan, Cheng Ean Chee, Chin Hin Ng, Jean Paul Thiery, Eugene Shen Ann Yeo, Kam M. Hui, Wee Joo Chng, Clarinda Chua, Edmund Chiong, Jianbiao Zhou, Sim Mei Yi, Boon Cher Goh, Jie Li, and Lee Kong Chian School of Medicine (LKCMedicine)
Tumor-specific antibody drugs can serve as cancer therapy with minimal side effects. A humanized antibody, PRL3-zumab, specifically binds to an intracellular oncogenic phosphatase PRL3, which is frequently expressed in several cancers. Here we show that PRL3-zumab specifically inhibits PRL3+ cancer cells in vivo, but not in vitro. PRL3 antigens are detected on the cell surface and outer exosomal membranes, implying an ‘inside-out’ externalization of PRL3. PRL3-zumab binds to surface PRL3 in a manner consistent with that in classical antibody-dependent cell-mediated cytotoxicity or antibody-dependent cellular phagocytosis tumor elimination pathways, as PRL3-zumab requires an intact Fc region and host FcγII/III receptor engagement to recruit B cells, NK cells and macrophages to PRL3+ tumor microenvironments. PRL3 is overexpressed in 80.6% of 151 fresh-frozen tumor samples across 11 common cancers examined, but not in patient-matched normal tissues, thereby implicating PRL3 as a tumor-associated antigen. Targeting externalized PRL3 antigens with PRL3-zumab may represent a feasible approach for anti-tumor immunotherapy., Phosphatase of regenerating liver 3 (PRL3) is usually found intracellularly, and is over-expressed in cancer cells. Here the authors show that PRL-3 is also detectable on cell surface, and can be recognized by PRL3-zumab to recruit immune cells into tumor to promote anti-tumor immunity, thereby implicating PRL-3 as a potential tumor antigen.