PRL3-zumab as an immunotherapy to inhibit tumors expressing PRL3 oncoprotein

Abstract

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.

Protein tyrosine phosphatase 4A3 (PTP4A3/PRL-3) drives migration and progression of T-cell acute lymphoblastic leukemia in vitro and in vivo

“…Protein tyrosine phosphatase 4A3 (PTP4A3), also known as phosphatase of regenerating liver 3 (PRL-3), is an oncogenic phosphatase that has received significant attention as a potential therapeutic target in a variety of cancers 7,8,10 . PRL-3 is highly expressed in~80% of 151 human tumor tissue samples across 11 tumor types, including liver, lung, colon, breast, stomach, thyroid, pancreas, kidney, bladder, and prostate cancer 10 , and PRL-3 has been extensively reported as a biomarker of tumor progression and metastasis in breast 11 , colon 12,13 , gastric 14 , brain 15 , and prostate 16 cancers. Elevated PRL-3 correlates with reduced survival in patients with breast 17 , gastric 14 , ovarian 18 , and liver 19 cancers and in acute myelogenous leukemia (AML) 20,21 .…”

Protein Tyrosine Phosphatase 4A3 (PTP4A3) modulates Src signaling in T-cell Acute Lymphoblastic Leukemia to promote leukemia migration and progression

“…While all of these small molecules target the entire PTP4A family, including PTP4A1, PTP4A2, and PTP4A3, the anti-cancer effects of these inhibitors have been demonstrated in cancer cells or xenotransplantation models. In addition, Qi Zeng's group has successfully developed humanized PTP4A3 antibody, which can specifically target PTP4A3 expressing tumors but not PTP4A1 expressing tumors [20,39]. These efforts support the concept that phosphatases are in fact druggable and suggest that PTP4A3 is a feasible therapeutic target in cancer.…”

“…PTP4A3 has been extensively reported as a biomarker of tumor progression and metastasis; for example, PTP4A3 expression is documented to be significantly elevated in tumor tissues compared with healthy tissues, and in advanced metastatic versus early stage tumors across a variety of solid tumor types, including breast [11], colon [12,13], gastric [14], brain [15], and prostate [16] as well as in Acute Myelogenous Leukemia (AML) [15,[17][18][19]. Similarly, PTP4A3 protein was recently shown to be highly expressed in ~80% of 151 human tumor samples across 11 varied tumor types, including liver, lung, colon, breast, stomach, thyroid, pancreas, kidney, AML, bladder and prostate [20]. Elevated PTP4A3 correlates with reduced survival in patients with breast [21], gastric [22], ovarian [23], and liver [24] cancers and in AML [25,26].…”

A screen of FDA-approved drugs identifies inhibitors of Protein Tyrosine Phosphatase 4A3 (PTP4A3 or PRL-3)

“…However, the solubility of JMS-053 is poor, and it requires further study to determine pharmacokinetics, toxicity, and efficacy in humans. Finally, a specific PRL-3 binding antibody has been developed, which is currently the only inhibitor capable of selectively targeting PRL-3 over other family members and is capable of preventing tumor growth using in vivo model of both hepatic and gastric cancers 15,49 .…”

“…In particular, PRL-3 is a well-defined biomarker of metastasis in multiple cancer types, including melanoma, colorectal, and ovarian cancers, where PRL-3 expression is significantly higher in metastatic lesions compared to the primary tumor site [6][7][8][9][10][11][12][13][14] . In a comprehensive study of 151 patient samples across eleven common human tumors types, PRL-3 protein expression was upregulated in 80.6% of tumor samples compared to matched normal tissue 15 . High PRL-3 expression is also associated with worse prognosis in human leukemia, breast, gastric, ovarian, and colorectal cancer 8,[16][17][18][19] .…”