caa a22 4500 605542996 CHVBK 20210128100924.0 cr unu---uuuuu 210128e20150601xx s 000 0 eng 10.1007/s00109-015-1280-4 doi (NATIONALLICENCE)springer-10.1007/s00109-015-1280-4 Retargeting pre-existing human antibodies to a bacterial pathogen with an alpha-Gal conjugated aptamer [Elektronische Daten] [Sascha Kristian, John Hwang, Bradley Hall, Emma Leire, John Iacomini, Robert Old, Uri Galili, Charles Roberts, Kary Mullis, Mike Westby, Victor Nizet] 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. Key Messages: • 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. Springer-Verlag Berlin Heidelberg, 2015 Aptamer nationallicence Galactose-α-1,3-galactosyl-β-1,4- N -acetyl-glucosamine nationallicence α-Gal nationallicence Anti-Gal nationallicence Antibiotic therapy nationallicence Drug development nationallicence Antibodies nationallicence Group A Streptococcus nationallicence M protein nationallicence Phagocytosis nationallicence Kristian Sascha Altermune Technologies, LLC, Irvine, CA, USA aut Hwang John BS/MS Program, Division of Biological Sciences, University of California San Diego (UCSD), La Jolla, CA, USA aut Hall Bradley Altermune Technologies, LLC, Irvine, CA, USA aut Leire Emma Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA, USA aut Iacomini John Sackler School of Biomedical Sciences Programs in Immunology and Genetics, Department of Development, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA aut Old Robert Loxbridge Research, The Royal Institution of Great Britain, London, UK aut Galili Uri Department of Surgery, University of Massachusetts Medical School, Worcester, MA, USA aut Roberts Charles Altermune Technologies, LLC, Irvine, CA, USA aut Mullis Kary Altermune Technologies, LLC, Irvine, CA, USA aut Westby Mike Altermune Technologies, LLC, Irvine, CA, USA aut Nizet Victor Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA, USA aut Journal of Molecular Medicine Springer Berlin Heidelberg 93/6(2015-06-01), 619-631 0946-2716 93:6<619 2015 93 109 https://doi.org/10.1007/s00109-015-1280-4 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00109-015-1280-4 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kristian Sascha Altermune Technologies, LLC, Irvine, CA, USA aut NATIONALLICENCE 700 1- Hwang John BS/MS Program, Division of Biological Sciences, University of California San Diego (UCSD), La Jolla, CA, USA aut NATIONALLICENCE 700 1- Hall Bradley Altermune Technologies, LLC, Irvine, CA, USA aut NATIONALLICENCE 700 1- Leire Emma Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA, USA aut NATIONALLICENCE 700 1- Iacomini John Sackler School of Biomedical Sciences Programs in Immunology and Genetics, Department of Development, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA aut NATIONALLICENCE 700 1- Old Robert Loxbridge Research, The Royal Institution of Great Britain, London, UK aut NATIONALLICENCE 700 1- Galili Uri Department of Surgery, University of Massachusetts Medical School, Worcester, MA, USA aut NATIONALLICENCE 700 1- Roberts Charles Altermune Technologies, LLC, Irvine, CA, USA aut NATIONALLICENCE 700 1- Mullis Kary Altermune Technologies, LLC, Irvine, CA, USA aut NATIONALLICENCE 700 1- Westby Mike Altermune Technologies, LLC, Irvine, CA, USA aut NATIONALLICENCE 700 1- Nizet Victor Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA, USA aut NATIONALLICENCE 773 0- Journal of Molecular Medicine Springer Berlin Heidelberg 93/6(2015-06-01), 619-631 0946-2716 93:6<619 2015 93 109