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.

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Macrophage migration inhibitory factor (MIF) was found to be upregulated in many cancers and to act in para- and autocrine loops within the tumor microenvironment. Thereby, MIF contributes to the modulation of cytokine patterns and triggers anti-apoptotic and pro-proliferative cell signaling events. MIF was also described as a pro-angiogenic factor promoting neoangiogenesis and vascularization. In prostate cancer, MIF mRNA and protein levels were shown to be increased and to contribute to tumor development. We have discovered a novel, previously unrecognized conformational isoform of MIF (designated ‘active MIF’) that is produced in diseases and cannot be detected in healthy subjects. A set of phage display derived human monoclonal anti-MIF antibodies neutralizing MIF biological activity in vitro and in vivo specifically recognize active MIF. In vitro, these antibodies elicited both, a growth inhibitory effect and a pro-apoptotic response on PC3 and DU145 prostate cancer cells by interfering with ERK1/2 and Akt/PKB signaling pathways and by promoting activation of caspase-3. Furthermore, the antibodies inhibited tumor cell invasion of PC3 cells in a transwell assay in a dose-dependent manner. In vivo, treatment with human antibodies specific for active MIF dose-dependently inhibited the growth of the human prostate cancer cell line PC3 xenografted into MF1 nude mice. New ELISA methods have been established to allow the detection of active MIF as well as non-active MIF in plasma samples. In the plasma of PC3 xenografted nude mice, we observed a reduction of active MIF upon antibody treatment. In addition we were able to prove the occurrence of active MIF in the plasma of prostate cancer patients (median 2445 pg/mL, p < 0.002 versus controls), whereas active MIF was not detectable in plasma from healthy donors. These studies demonstrate that active MIF represents a new target in prostate cancer, as well as a promising marker for disease activity or disease progression. The data further suggest that our fully human anti-MIF antibodies have a good potential for clinical use in oncology. Citation Format: Michael Thiele, Michael Freissmuth, Filza Hussain, Patrice Douillard, Dirk Völkel, Hartmut Ehrlich, Friedrich Scheiflinger, Randolf Kerschbaumer. Human antibodies specific for a novel isoform of the macrophage migration inhibitory factor are potential therapeutics for prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1235. doi:10.1158/1538-7445.AM2013-1235

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