Randolf J Kerschbaumer

Publications (2)10 Total impact

• Article: Human Anti-Macrophage Migration Inhibitory Factor (MIF) Antibodies Inhibit Growth of Human Prostate Cancer Cells In Vitro and In Vivo.

  Filza Hussain, Michael Freissmuth, Dirk Volkel, Michael Thiele, Patrice Douillard, Gerhard Antoine, Patrick Thurner, Hartmut Ehrlich, Hans-Peter Schwarz, Friedrich Scheiflinger, Randolf J Kerschbaumer
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  ABSTRACT: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine, originally discovered for its eponymous effect and now known for pleiotropic biological 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 (ERK1/2) and protein kinase B (AKT). Incubation of cells in the presence of the antibodies also promoted activation of caspases 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.
  Molecular Cancer Therapeutics 04/2013; · 5.23 Impact Factor
• Article: Neutralization of macrophage migration inhibitory factor (MIF) by fully human antibodies correlates with their specificity for the β-sheet structure of MIF.

  Randolf J Kerschbaumer, Manfred Rieger, Dirk Völkel, Didier Le Roy, Thierry Roger, Jurate Garbaraviciene, Wolf-Henning Boehncke, Jürgen Müllberg, Rene M Hoet, Clive R Wood, Gerhard Antoine, Michael Thiele, Helga Savidis-Dacho, Michael Dockal, Hartmut Ehrlich, Thierry Calandra, Friedrich Scheiflinger
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  ABSTRACT: The macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that recently emerged as an attractive therapeutic target for a variety of diseases. A diverse panel of fully human anti-MIF antibodies was generated by selection from a phage display library and extensively analyzed in vitro. Epitope mapping studies identified antibodies specific for linear as well as structural epitopes. Experimental animal studies revealed that only those antibodies binding epitopes within amino acids 50-68 or 86-102 of the MIF molecule exerted protective effects in models of sepsis or contact hypersensitivity. Within the MIF protein, these two binding regions form a β-sheet structure that includes the MIF oxidoreductase motif. We therefore conclude that this β-sheet structure is a crucial region for MIF activity and a promising target for anti-MIF antibody therapy.
  Journal of Biological Chemistry 03/2012; 287(10):7446-55. · 4.77 Impact Factor