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Improving the Therapeutic Potential of Human Granzyme B for Targeted Cancer Therapy
Pharmedartis GmbH, Aachen 52074, Germany
Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, University Hospital RWTH Aachen, Aachen 52074, Germany
Department of Pharmaceutical Product Development, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen 52074, Germany
These author contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 13 December 2012; in revised form: 4 January 2013 / Accepted: 8 January 2013 / Published: 16 January 2013
Abstract: Conventional cancer treatments lack specificity and often cause severe side effects. Targeted therapeutic approaches are therefore preferred, including the use of immunotoxins (ITs) that comprise cell-binding and cell death-inducing components to allow the direct and specific delivery of pro-apoptotic agents into malignant cells. The first generation of ITs consisted of toxins derived from bacteria or plants, making them immunogenic in humans. The recent development of human cytolytic fusion proteins (hCFP) consisting of human effector enzymes offers the prospect of highly-effective targeted therapies with minimal side effects. One of the most promising candidates is granzyme B (GrB) and this enzyme has already demonstrated its potential for targeted cancer therapy. However, the clinical application of GrB may be limited because it is inactivated by the overexpression in tumors of its specific inhibitor serpin B9 (PI-9). It is also highly charged, which means it can bind non-specifically to the surface of non-target cells. Furthermore, human enzymes generally lack an endogenous translocation domain, thus the endosomal release of GrB following receptor-mediated endocytosis can be inefficient. In this review we provide a detailed overview of these challenges and introduce promising solutions to increase the cytotoxic potency of GrB for clinical applications.
Keywords: immunotherapy; immunotoxin; human cytolytic fusion protein; bio-engineering; serpin B9; surface-charge; endosomal release
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Hehmann-Titt, G.; Schiffer, S.; Berges, N.; Melmer, G.; Barth, S. Improving the Therapeutic Potential of Human Granzyme B for Targeted Cancer Therapy. Antibodies 2013, 2, 19-49.
Hehmann-Titt G, Schiffer S, Berges N, Melmer G, Barth S. Improving the Therapeutic Potential of Human Granzyme B for Targeted Cancer Therapy. Antibodies. 2013; 2(1):19-49.
Hehmann-Titt, Grit; Schiffer, Sonja; Berges, Nina; Melmer, Georg; Barth, Stefan. 2013. "Improving the Therapeutic Potential of Human Granzyme B for Targeted Cancer Therapy." Antibodies 2, no. 1: 19-49.