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Diving through Membranes: Molecular Cunning to Enforce the Endosomal Escape of Antibody-Targeted Anti-Tumor Toxins
Institute for Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin 12200, Germany
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
The Simon Flavell Leukaemia Research Unit, Southampton General Hospital, Southampton SO16 6YD, UK
* Author to whom correspondence should be addressed.
Received: 4 March 2013; in revised form: 27 March 2013 / Accepted: 5 April 2013 / Published: 17 April 2013
Abstract: Membranes are vital barriers by which cells control the flux of molecules and energy between their exterior and interior and also between their various intracellular compartments. While numerous transport systems exist for ions and small molecules, the cytosolic uptake of larger biological molecules and in particular antibody-targeted drugs, is a big challenge. Inducing leakage of the plasma membrane is unfavorable since the target cell specificity mediated by the antibody would likely be lost in this case. After binding and internalization, the antibody drug conjugates reach the endosomes. Thus, enforcing the endosomal escape of anti-tumor toxins without affecting the integrity of other cellular membranes is of paramount importance. Different strategies have been developed in the last decades to overcome endosomal accumulation and subsequent lysosomal degradation of targeted protein-based drugs. In this review we summarize the various efforts made to establish efficient techniques to disrupt the endosomal membrane barrier including the use of molecular ferries such as cell penetrating peptides or viral membrane fusion proteins, endosomal leakage inducing molecules such as saponins or monensin and physicochemical methods as represented by photochemical internalization.
Keywords: targeted tumor therapies; endosomal escape; cell penetrating peptides; viral membrane fusion proteins; saponin; monensin; chloroquine; polyethylenimine; photochemical internalization
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Fuchs, H.; Bachran, C.; Flavell, D.J. Diving through Membranes: Molecular Cunning to Enforce the Endosomal Escape of Antibody-Targeted Anti-Tumor Toxins. Antibodies 2013, 2, 209-235.
Fuchs H, Bachran C, Flavell DJ. Diving through Membranes: Molecular Cunning to Enforce the Endosomal Escape of Antibody-Targeted Anti-Tumor Toxins. Antibodies. 2013; 2(2):209-235.
Fuchs, Hendrik; Bachran, Christopher; Flavell, David J. 2013. "Diving through Membranes: Molecular Cunning to Enforce the Endosomal Escape of Antibody-Targeted Anti-Tumor Toxins." Antibodies 2, no. 2: 209-235.