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

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.

Effect of blood type on anti-α-Gal immunity and the incidence of infectious diseases

“…Retargeting pre-existing anti-α-Gal antibodies to pathogens with an alpha-Gal-conjugated aptamer could be developed as a novel therapeutic approach. 38 In addition, the recent finding that increased abundance of α-Gal producing bacteria, Lactobacillus and Bifidobacterium in the gut microbiota affects Plasmodium infection in mice. 39 This opens the possibility of using probiotics as potential interventions to reduce disease severity, which may also be conditioned by blood type in humans.…”

Glycomics: revealing the dynamic ecology and evolution of sugar molecules

“…Alpha gal antibodies also prevent organ transplantation from other mammal species – pig organs are rejected partly because they are rich in alpha gal [66]. Anti alpha gal antibodies have a potential medical applications if they could be directed against pathogens or cancerous cells [67]. …”

Aptamer‐integrated α‐Gal liposomes as bispecific agents to trigger immune response for killing tumor cells

“…We chose the mouse laminin as a positive control since it is a crude glycoprotein with multiple α‐Gal epitopes. The Apt‐Lips, Lips, and mouse laminin were immobilized on 96‐well microplates and titrated by a serial dilution of hIVIG, which contains anti‐Gal antibodies . HRP conjugated anti‐human IgG antibody was used to detect the binding of anti‐Gal IgG.…”

“…The Apt-Lips, Lips, and mouse laminin were immobilized on 96-well microplates and titrated by a serial dilution of hIVIG, which contains anti-Gal antibodies. 44 HRP conjugated anti-human IgG antibody was used to detect the binding of anti-Gal IgG. As shown in Supporting Information Figure S3, human IgG had similar binding efficiency to Apt-Lips, Lips, and mouse laminins.…”