Linkoping University Sweden
Title: Mangafodipir (MnDPDP) from bench to bedside
Jan Olof G. Karlsson has a PhD from Linköping University. Between 1990 and 1992 he held a position as a research fellow at the Swedish Medical Research Council. Thereafter he worked as a senior scientist for Nycomed Imaging, which later became GE Healthcare, until 2007. At present he is a scientific advisor at PledPharma AB. Karlsson has published 75 scientific papers and is inventor of 9 issued patent families. During the early 1990’s Karlsson was involved in research showing that the MRI contrast agent mangafodipir possesses SOD-mimetic activity, a potentially useful property in treatment of several pathological conditions.
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) participate in tissue damage, caused by e.g., ischemia-reperfusion, inflammation, drugs and radiation. The mitochondrial superoxide dismutase (MnSOD) plays a key role in keeping ROS and RNS in check. During development of MnDPDP as an MRI contrast agent it was serendipitously discovered that MnDPDP and its metabolite MnPLED possessed MnSOD mimetic activity. Subsequently it was shown that it protected mice against serious side effects of several chemotherapy drugs, without interfering negatively with the anticancer effect. The compound was first tried in a colon cancer patient going through palliative treatment with 5-FU plus oxaliplatin. A first clinical feasibility study in colon cancer patients going through adjuvant 5-FU plus oxaliplatin reported promising results in 2012. This was followed by another clinical feasibility study showing encouraging results when it comes to treatment of neuropathy caused by oxaliplatin. MnPLED has furthermore been shown to reduce myocardial infarction size in a pig model, and MnDPDP was recently tested as an adjunct to PCI in patients with ST-elevated myocardial infarctions, with promising results. MnDPDP has also been shown protect mice against acetaminophen-induced liver failure. Whereas MRI contrast depends on release of Mn2+, the MnSOD mimetic activity depends on Mn2+ still bound to DPDP or PLED. Calmangafodipir [Ca4Mn(DPDP)5] is stabilized with respect to Mn2+ and has at equimolar Mn2+ doses superior therapeutic activity in comparison to MnDPDP. Ca4Mn(DPDP)5 is at present explored as a chemotherapy adjunct in a clinical multicenter phase II study in patients with metastatic colorectal cancer.