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Retargeting pre-existing human antibodies to a bacterial pathogen with an alpha-Gal conjugated aptamer

Authors :
Charles Edward Selkirk Roberts
Sascha A. Kristian
Emma Leire
Bradley Hall
Kary B. Mullis
Robert Old
Uri Galili
John Iacomini
Victor Nizet
John H. Hwang
Mike Westby
Source :
Journal of Molecular Medicine. 93:619-631
Publication Year :
2015
Publisher :
Springer Science and Business Media LLC, 2015.

Abstract

The ever-increasing threat of multi-drug resistant bacterial infections has spurred renewed interest in alternative approaches to classical antibiotic therapy. In contrast to other mammals, humans do not express the galactose-α-1,3-galactosyl-β-1,4-N-acetyl-glucosamine (α-Gal) epitope. As a result of exposure of humans to α-Gal in the environment, a large proportion of circulating antibodies are specific for the trisaccharide. In this study, we examine whether these anti-Gal antibodies can be recruited and redirected to exert anti-bacterial activity. We show that a specific DNA aptamer conjugated to an α-Gal epitope at its 5′ end, herein termed an alphamer, can bind to group A Streptococcus (GAS) bacteria by recognition of a conserved region of the surface-anchored M protein. The anti-GAS alphamer was shown to recruit anti-Gal antibodies to the streptococcal surface in an α-Gal-specific manner, elicit uptake and killing of the bacteria by human phagocytes, and slow growth of invasive GAS in human whole blood. These studies provide a first in vitro proof of concept that alphamers have the potential to redirect pre-existing antibodies to bacteria in a specific manner and trigger an immediate antibacterial immune response. Further validation of this novel therapeutic approach of applying α-Gal technology in in vivo models of bacterial infection is warranted. • α-Gal-tagged aptamers lead to GAS opsonization with anti-Gal antibodies. • α-Gal-tagged aptamers confer phagocytosis and killing of GAS cells by human phagocytes. • α-Gal-tagged aptamers reduces replication of GAS in human blood. • α-Gal-tagged aptamers may have the potential to be used as novel passive immunization drugs.

Details

ISSN :
14321440 and 09462716
Volume :
93
Database :
OpenAIRE
Journal :
Journal of Molecular Medicine
Accession number :
edsair.doi.dedup.....89e4c18c47d7c949b60d24012e930b91
Full Text :
https://doi.org/10.1007/s00109-015-1280-4