Human anti-MIF 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 its pleiotropic properties, in particular for its ability to override the action of glucocorticoids. Circulating MIF levels are elevated in several types of human cancer including prostate cancer. MIF is released presumably by both, stromal and tumour cells and enhances malignant growth and metastasis by diverse mechanisms, e.g., by (i) stimulating tumour cell proliferation, (ii) suppressing apoptotic death, (iii) facilitating invasion of the extracellular matrix. Recently developed 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 and inhibited MIF-promoted invasion/chemokinesis. The antibodies inhibited MIF-induced phosphorylation of ERK1/2 (=mitogen-activated protein kinase) and AKT. Incubation of cells in the presence of the antibody also promoted activation of caspases 3/7. Pharmacokinetic parameters (half-life, volume of distribution and bioavailability) of the antibodies were determined and an in vivo proof of concept was obtained by injecting 2x106 PC3 cells subcutaneously into the flank of MF-1 nude mice: treatment with human anti-MIF antibodies blunted xenograft tumour growth in a dose-dependent manner. These observations support the conclusion that anti-MIF antibodies neutralize the proliferative actions of MIF and thus limit tumour growth in vivo.submitted by Filza HussainAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersZsfassung in dt. SpracheWien, Med. Univ., Diss., 2012OeBB(VLID)188343