title: Human anti-macrophage migration inhibitory factor antibodies inhibit growth of human prostate cancer cells in vitro and in vivo.
abstract: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine, originally discovered for its eponymous effect and now known for pleiotropic biologic properties in immunology and oncology. Circulating MIF levels are elevated in several types of human cancer including prostate cancer. MIF is released presumably by both stromal and tumor cells and enhances malignant growth and metastasis by diverse mechanisms, such as stimulating tumor cell proliferation, suppressing apoptotic death, facilitating invasion of the extracellular matrix, and promoting angiogenesis. Recently described fully human anti-MIF antibodies were tested in vitro and in vivo for their ability to influence growth rate and invasion of the human PC3 prostate cancer cell line. In vitro, the selected candidate antibodies BaxG03, BaxB01, and BaxM159 reduced cell growth and viability by inhibiting MIF-induced phosphorylation of the central kinases p44/42 mitogen-activated protein kinase [extracellular signal-regulated kinase-1 and -2 (ERK1/2)] and protein kinase B (AKT). Incubation of cells in the presence of the antibodies also promoted activation of caspase-3/7. The antibodies furthermore inhibited MIF-promoted invasion and chemotaxis as transmigration through Matrigel along a MIF gradient was impaired. In vivo, pharmacokinetic parameters (half-life, volume of distribution, and bioavailability) of the antibodies were determined and a proof-of-concept was obtained in a PC3-xenograft mouse model. Treatment with human anti-MIF antibodies blunted xenograft tumor growth in a dose-dependent manner. We therefore conclude that the anti-MIF antibodies described neutralize some of the key tumor-promoting activities of MIF and thus limit tumor growth in vivo.
authors.affiliation: Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University Vienna, Währinger Str. 13a, 1090 Vienna, Austria.
authors.forename: Filza
authors.initials: F
authors.lastname: Hussain
authors.forename: Michael
authors.initials: M
authors.lastname: Freissmuth
authors.forename: Dirk
authors.initials: D
authors.lastname: Völkel
authors.forename: Michael
authors.initials: M
authors.lastname: Thiele
authors.forename: Patrice
authors.initials: P
authors.lastname: Douillard
authors.forename: Gerhard
authors.initials: G
authors.lastname: Antoine
authors.forename: Patrick
authors.initials: P
authors.lastname: Thurner
authors.forename: Hartmut
authors.initials: H
authors.lastname: Ehrlich
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Schwarz
authors.forename: Friedrich
authors.initials: F
authors.lastname: Scheiflinger
authors.forename: Randolf J
authors.initials: RJ
authors.lastname: Kerschbaumer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000276:immunology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D008263:Macrophage Migration-Inhibitory Factors