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


CONCLUSIONS
. 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.
Altermune Technologies, LLC, Irvine, CA, USA.
Sascha A
SA
Kristian
John H
JH
Hwang
Bradley
B
Hall
Emma
E
Leire
John
J
Iacomini
Robert
R
Old
Uri
U
Galili
Charles
C
Roberts
Kary B
KB
Mullis
Mike
M
Westby
Victor
V
Nizet
D000117:Acetylglucosamine / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D000907:Antibodies, Bacterial / Q000276:immunology*; D052157:Aptamers, Nucleotide / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D001483:Base Sequence; D055808:Drug Discovery; D000939:Epitopes / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D008969:Molecular Sequence Data; D010587:Phagocytosis / Q000187:drug effects; D013290:Streptococcal Infections / Q000188:drug therapy* / Q000276:immunology; D013291:Streptococcus / Q000187:drug effects* / Q000276:immunology
D000900:Anti-Bacterial Agents; D000907:Antibodies, Bacterial; D052157:Aptamers, Nucleotide; D000939:Epitopes; D000117:Acetylglucosamine