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2015 ; 93
(6
): 619-31
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Retargeting pre-existing human antibodies to a bacterial pathogen with an
alpha-Gal conjugated aptamer
#MMPMID25940316
Kristian SA
; Hwang JH
; Hall B
; Leire E
; Iacomini J
; Old R
; Galili U
; Roberts C
; Mullis KB
; Westby M
; Nizet V
J Mol Med (Berl)
2015[Jun]; 93
(6
): 619-31
PMID25940316
show ga
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-?-1,3-galactosyl-?-1,4-N-acetyl-glucosamine (?-Gal) epitope. As a
result of exposure of humans to ?-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 ?-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 ?-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 ?-Gal
technology in in vivo models of bacterial infection is warranted. KEY MESSAGES: .
?-Gal-tagged aptamers lead to GAS opsonization with anti-Gal antibodies. .
?-Gal-tagged aptamers confer phagocytosis and killing of GAS cells by human
phagocytes. . ?-Gal-tagged aptamers reduces replication of GAS in human blood. .
?-Gal-tagged aptamers may have the potential to be used as novel passive
immunization drugs.
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