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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal, Humanized
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Antibodies, Monoclonal, Murine-Derived
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Antibody-Dependent Cell Cytotoxicity / drug effects*
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Antigens, Neoplasm / metabolism
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Antineoplastic Agents, Immunological / pharmacology*
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B-Lymphocytes
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Carcinoma, Hepatocellular / metabolism*
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Cell Line, Tumor
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Cytophagocytosis / drug effects*
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Hep G2 Cells
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Hepatocytes / drug effects*
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Hepatocytes / metabolism
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Humans
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Immunotherapy
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Killer Cells, Natural
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Liver Neoplasms / metabolism*
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Macrophages
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Mice
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Molecular Targeted Therapy
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / metabolism
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Neoplasm Transplantation
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Neoplasms / metabolism
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Oncogene Proteins / metabolism
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Protein Tyrosine Phosphatases / antagonists & inhibitors*
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Protein Tyrosine Phosphatases / metabolism
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Receptors, IgG
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Tumor Microenvironment / drug effects*
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Tumor Microenvironment / immunology
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Monoclonal, Humanized
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Antibodies, Monoclonal, Murine-Derived
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Antigens, Neoplasm
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Antineoplastic Agents, Immunological
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Neoplasm Proteins
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Oncogene Proteins
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Receptors, IgG
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PTP4A3 protein, human
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Protein Tyrosine Phosphatases