The strong in vivo anti-tumor effect of the UIC2 monoclonal antibody is the combined result of Pgp inhibition and antibody dependent cell-mediated cytotoxicity

• Published in: PloS one 2014-09, Vol.9 (9), p.e107875
• Main Authors: Szalóki, Gábor, Krasznai, Zoárd T, Tóth, Ágnes, Vízkeleti, Laura, Szöllősi, Attila G, Trencsényi, György, Lajtos, Imre, Juhász, István, Krasznai, Zoltán, Márián, Teréz, Balázs, Margit, Szabó, Gábor, Goda, Katalin
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Antibody-Dependent Cell Cytotoxicity - drug effects; Antibody-Dependent Cell Cytotoxicity - physiology; Anticancer properties; Antineoplastic Agents - pharmacology; Antitumor activity; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - immunology; Biocompatibility; Biological products; Biological Transport; Biology; Biology and Life Sciences; Biophysics; Blood-brain barrier; Breast cancer; Cancer therapies; Cell Line, Tumor; Cell surface; Chemotherapy; Cyclosporine - pharmacology; Cyclosporins; Cytotoxicity; Doxorubicin; Doxorubicin - pharmacology; Drug resistance; Drug Resistance, Multiple; Drug Synergism; Drugs; Epidermal growth factor; Glucose; Glycoproteins; Humans; Immunodeficiency; Immunoglobulins; Immunology; Immunomodulation; Inhibition; Leukocytes (mononuclear); Medical imaging; Medicine and Health Sciences; Metabolism; Mice, SCID; Modulators; Monoclonal antibodies; Multidrug resistance; Nuclear medicine; P-Glycoprotein; Peripheral blood mononuclear cells; Positron emission; Positron emission tomography; Preventive medicine; Proteins; Research and Analysis Methods; Severe combined immunodeficiency; Substrates; Tomography; Toxicity; Tumors; Viability; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0107875

P-glycoprotein (Pgp) extrudes a large variety of chemotherapeutic drugs from the cells, causing multidrug resistance (MDR). The UIC2 monoclonal antibody recognizes human Pgp and inhibits its drug transport activity. However, this inhibition is partial, since UIC2 binds only to 10-40% of cell surface Pgps, while the rest becomes accessible to this antibody only in the presence of certain substrates or modulators (e.g. cyclosporine A (CsA)). The combined addition of UIC2 and 10 times lower concentrations of CsA than what is necessary for Pgp inhibition when the modulator is applied alone, decreased the EC50 of doxorubicin (DOX) in KB-V1 (Pgp+) cells in vitro almost to the level of KB-3-1 (Pgp-) cells. At the same time, UIC2 alone did not affect the EC50 value of DOX significantly. In xenotransplanted severe combined immunodeficient (SCID) mice co-treated with DOX, UIC2 and CsA, the average weight of Pgp+ tumors was only ∼10% of the untreated control and in 52% of these animals we could not detect tumors at all, while DOX treatment alone did not decrease the weight of Pgp+ tumors. These data were confirmed by visualizing the tumors in vivo by positron emission tomography (PET) based on their increased 18FDG accumulation. Unexpectedly, UIC2+DOX treatment also decreased the size of tumors compared to the DOX only treated animals, as opposed to the results of our in vitro cytotoxicity assays, suggesting that immunological factors are also involved in the antitumor effect of in vivo UIC2 treatment. Since UIC2 binding itself did not affect the viability of Pgp expressing cells, but it triggered in vitro cell killing by peripheral blood mononuclear cells (PBMCs), it is concluded that the impressive in vivo anti-tumor effect of the DOX-UIC2-CsA treatment is the combined result of Pgp inhibition and antibody dependent cell-mediated cytotoxicity (ADCC).