Abstract
The modification of the Immunoglobulin Fc part offers various ways to improve the efficacy of naïve IgG for tumor therapy. Here we describe a strategy based on the addition a new effector function, which allows a different therapeutic paradigm. This approach was hampered for decades by the lack of human fusion partners as effectors. For example, many immunotoxins have been designed and tested, but all to often caused severe side effects due to their immunogenicity and/or unspecific toxicity. Further, their production frequently requires refolding steps. Here, human effector domains may better be employed to avoid these disadvantages.
A now well established class of effectors are RNases. They are usually non-toxic while in circulation but highly effective in cell killing after internalization. We engineered and succesfully produced in mammalian cells an entirely human immunoenzyme directed against CD30+ lymphomas. It was constructed from an scFv-Fc antibody fragmennt and a human RNase. It did not affect the human embryonlal kidney cells used for its production by secretion of active molecules into the supernatant at concentrations up to 60mg/L, but strongly inhibited proliferation of CD30+ lymphoma cells with an IC50 = 3,3 nM. Our design also improved resistence to RNase inhibitor without the necessity to mutate the human RNase sequence, thus eliminating the risk of added immunogenicity from this end.
About the Speaker
Stefan Duebel is Full Professor of Biotechnology and Director of the respective department at the Technical University of Braunschweig, Germany. Prof Duebel serves in boards of scientific journals and as consultant to biotech and pharma companies. Further, he is initiator of the "Antibody factory" of the German National Gemome Research Network and editor of the three volume "Handbook of Therapeutic Antibodies" and other antibody engineering books.
After obtaining his PhD from the Universitiy of Heidelberg in 1989, Prof Duebel joined the German Cancer Research Center (DKFZ) where he co-pioneered in vitro antibody selection technologies, resulting in several key inventions including antibody phage display and antibody libraries with randomised CDRs. His lab continued to contribute to multiple topics related to human antibody engineering and phage display, e.g. Hyperphage technology (2001), single chain Fab fragments (2006) and targeted RNases for cancer therapy (2008). Methods pioneered by him are now widely used and well established in academic as well as commercial laboratories. Further contributions were made to the fields of human IgG production, infectious disease reserach, novel recombinant production systems (e.g. in Bacillus megaterium), high throughput antibody generation, intrabodies and nanobiotechnology. His work resulted in 150+ publications and 20+ patent applications.
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