Enhancement of polymeric immunoglobulin receptor transcytosis by biparatopic VHH

The polymeric immunoglobulin receptor (pIgR) ensures the transport of dimeric immunoglobulin A (dIgA) and pentameric immunoglobulin M (pIgM) across epithelia to the mucosal layer of for example the intestines and the lungs via transcytosis. Per day the human pIgR mediates the excretion of 2 to 5 gra...

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Published in:	PloS one Vol. 6; no. 10; p. e26299
Main Authors:	Emmerson, Chris D, van der Vlist, Els J, Braam, Myrthe R, Vanlandschoot, Peter, Merchiers, Pascal, de Haard, Hans J W, Verrips, C Theo, van Bergen en Henegouwen, Paul M P, Dolk, Edward
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 14-10-2011 Public Library of Science (PLoS)
Subjects:	Animals Antibodies Biology Caco-2 Cells Camelids, New World Cell Polarity Clustering Dogs Epithelial cells Epithelial Cells - cytology Epithelial Cells - metabolism Epitope Mapping Excretion Fc receptors Humans Immunoglobulin A Immunoglobulin Heavy Chains - metabolism Immunoglobulin M Immunoglobulin Variable Region - metabolism Immunoglobulins Intestine Kinases Ligands Lungs Medicine Mucosa Nanobodies Organs Permeability Phages Phenols PigR gene Protein Binding Receptor density Receptors, Polymeric Immunoglobulin - metabolism Reproducibility of Results Science Streptococcus infections Transcytosis Transport Belgium Netherlands
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Summary:	The polymeric immunoglobulin receptor (pIgR) ensures the transport of dimeric immunoglobulin A (dIgA) and pentameric immunoglobulin M (pIgM) across epithelia to the mucosal layer of for example the intestines and the lungs via transcytosis. Per day the human pIgR mediates the excretion of 2 to 5 grams of dIgA into the mucosa of luminal organs. This system could prove useful for therapies aiming at excretion of compounds into the mucosa. Here we investigated the use of the variable domain of camelid derived heavy chain only antibodies, also known as VHHs or Nanobodies®, targeting the human pIgR, as a transport system across epithelial cells. We show that VHHs directed against the human pIgR are able to bind the receptor with high affinity (∼1 nM) and that they compete with the natural ligand, dIgA. In a transcytosis assay both native and phage-bound VHH were only able to get across polarized MDCK cells that express the human pIgR gene in a basolateral to apical fashion. Indicating that the VHHs are able to translocate across epithelia and to take along large particles of cargo. Furthermore, by making multivalent VHHs we were able to enhance the transport of the compounds both in a MDCK-hpIgR and Caco-2 cell system, probably by inducing receptor clustering. These results show that VHHs can be used as a carrier system to exploit the human pIgR transcytotic system and that multivalent compounds are able to significantly enhance the transport across epithelial monolayers.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current address: Thrombogenics NV, Heverlee, Belgium Current address: Argen-X BV, Zwijnaarde, Belgium Conceived and designed the experiments: CDE EJvdV MRB PV PM HJWdH CTV PMPvBeH ED. Performed the experiments: CDE EJvdV MRB ED. Analyzed the data: CDE EJvdV MRB PV PM HJWdH CTV PMPvBeH ED. Contributed reagents/materials/analysis tools: CDE PV PM CTV PMPvBeH, ED. Wrote the paper: CDE CTV PMPvBeH ED.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0026299