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.

Selective Targeting of a Disease-Related Conformational Isoform of Macrophage Migration Inhibitory Factor Ameliorates Inflammatory Conditions

“…Human monoclonal anti-MIF Abs BaxB01, BaxG03, and BaxM159 were shown to neutralize MIF functional activity in cell-based assays and to be protective in animal models (30,31). However, surface plasmon resonance (SPR; Fig.…”

“…We recently described the fully human mAbs BaxB01, BaxG03, and BaxM159 that effectively inhibit the biological activity of MIF in vivo and in vitro (30,31). These Abs are specific for two distinct epitopes (aa 50-68 or 86-102), which form a b-barrel structure containing the highly conserved 57 Cys-Ala-Leu-Cys 60 -motif (30); this forms the catalytic motif of the thiol protein oxidoreductase linked to MIF's biologic function (32)(33)(34).…”

Trichomonas vaginalis homolog of macrophage migration inhibitory factor induces prostate cell growth, invasiveness, and inflammatory responses

“…Human macrophage migration inhibitory factor (HuMIF) has been implicated in a broad array of conditions associated with inflammation, including autoimmunity, cell proliferation, angiogenesis, and tumorigenesis (12)(13)(14)(15). Increased expression of HuMIF has been reported in several cancers, including prostate cancer (16)(17)(18). Studies show high expressers of HuMIF have a heightened risk of prostate cancer, as well as a significant increase in prostate cancer progression and drug resistance (17)(18)(19)(20)(21)(22)(23).…”

“…Increased expression of HuMIF has been reported in several cancers, including prostate cancer (16)(17)(18). Studies show high expressers of HuMIF have a heightened risk of prostate cancer, as well as a significant increase in prostate cancer progression and drug resistance (17)(18)(19)(20)(21)(22)(23). Several clinical studies have shown HuMIF production correlates with both tumor aggressiveness and metastatic potential (23,24).…”

Cell Proliferation and Epithelia Profile in Prostate Cancer and Benign Prostatic Hyperplasia

“…Adhesion, migration and tumor cell invasivenessespecially related to E-cadherin adhesion molecule; 3. Tumor angiogenesis -which can be immunochemically evaluated by CD34 expression [5,6].…”