Biosynthesis of α-Gal Epitopes (Galα1-3Galβ1-4GlcNAc-R) and Their Unique Potential in Future α-Gal Therapies

Abstract

The α-gal epitope is a carbohydrate antigen which appeared early in mammalian evolution and is synthesized in large amounts by the glycosylation enzyme α1,3galactosyltransferase (α1,3GT) in non-primate mammals, lemurs, and New-World monkeys. Ancestral Old-World monkeys and apes synthesizing α-gal epitopes underwent complete extinction 20–30 million years ago, and their mutated progeny lacking α-gal epitopes survived. Humans, apes, and Old-World monkeys which evolved from the surviving progeny lack α-gal epitopes and produce the natural anti-Gal antibody which binds specifically to α-gal epitopes. Because of this reciprocal distribution of the α-gal epitope and anti-Gal in mammals, transplantation of organs from non-primate mammals (e.g., pig xenografts) into Old-World monkeys or humans results in hyperacute rejection following anti-Gal binding to α-gal epitopes on xenograft cells. The in vivo immunocomplexing between anti-Gal and α-gal epitopes on molecules, pathogens, cells, or nanoparticles may be harnessed for development of novel immunotherapies (referred to as “α-gal therapies”) in various clinical settings because such immune complexes induce several beneficial immune processes. These immune processes include localized activation of the complement system which can destroy pathogens and generate chemotactic peptides that recruit antigen-presenting cells (APCs) such as macrophages and dendritic cells, targeting of antigens presenting α-gal epitopes for extensive uptake by APCs, and activation of recruited macrophages into pro-reparative macrophages. Some of the suggested α-gal therapies associated with these immune processes are as follows: 1. Increasing efficacy of enveloped-virus vaccines by synthesizing α-gal epitopes on vaccinating inactivated viruses, thereby targeting them for extensive uptake by APCs. 2. Conversion of autologous tumors into antitumor vaccines by expression of α-gal epitopes on tumor cell membranes. 3. Accelerating healing of external and internal injuries by α-gal nanoparticles which decrease the healing time and diminish scar formation. 4. Increasing anti-Gal–mediated protection against zoonotic viruses presenting α-gal epitopes and against protozoa, such as Trypanosoma, Leishmania, and Plasmodium, by vaccination for elevating production of the anti-Gal antibody. The efficacy and safety of these therapies were demonstrated in transgenic mice and pigs lacking α-gal epitopes and producing anti-Gal, raising the possibility that these α-gal therapies may be considered for further evaluation in clinical trials.

Sialylated and sulfated N-Glycans in MDCK and engineered MDCK cells for influenza virus studies

“…A non-human epitope with the composition of Gal-Gal-GlcNAc was observed especially on sialylated glycans (e.g., m/z 2809). This sequence is likely as the Galα1-3Galβ1-4GlcNAc sequence is commonly found at the non-reducing termini in glycans from many mammals and non-human primates 16 . An additional HexNAc, which was proposed to be a bisecting GlcNAc, was found on non-sialylated and sialylated structures (e.g., m/z 2489 and 3212).…”

The interaction between nanoparticles and immune system: application in the treatment of inflammatory diseases

“…The impaired healing of tissue damage caused by inflammatory diseases like diabetes and myocardial infarction is another serious clinical problem bringing huge public health burden, the mechanism of which has been linked to an inadequate response from macrophages [ 43 – 45 ]. The α-gal epitope (with the structure as Galα1-3Galβ1-4GlcNAc-R) is a carbohydrate antigen synthesized in non-primate mammals, lemurs, and New-World monkeys [ 46 ]. It can bind to its natural antibody, which are abundant in human body, and forms immune complexes that can recruit antigen-presenting cells (APCs) such as macrophages [ 46 ].…”

“…The α-gal epitope (with the structure as Galα1-3Galβ1-4GlcNAc-R) is a carbohydrate antigen synthesized in non-primate mammals, lemurs, and New-World monkeys [ 46 ]. It can bind to its natural antibody, which are abundant in human body, and forms immune complexes that can recruit antigen-presenting cells (APCs) such as macrophages [ 46 ]. Galili et al utilized α-gal nanoparticles prepared from rabbit red blood cell membranes to recruit pro-reparative macrophages to the infarcted territory in a mouse model of myocardial infarction.…”

α-Gal Nanoparticles Mediated Homing of Endogenous Stem Cells for Repair and Regeneration of External and Internal Injuries by Localized Complement Activation and Macrophage Recruitment

“…The production of the natural anti-Gal antibody in all humans provides a unique opportunity for harnessing the immunological potential of this antibody for development of novel therapies in various clinical settings. These therapies are called α-gal therapies because they use the α-gal epitope in different contexts in order to manipulate the anti-Gal antibody [ 49 ]. One of the tools developed for this purpose is α-gal nanoparticles [ 49 , 50 , 51 , 52 , 53 , 54 , 55 ].…”

“…These therapies are called α-gal therapies because they use the α-gal epitope in different contexts in order to manipulate the anti-Gal antibody [ 49 ]. One of the tools developed for this purpose is α-gal nanoparticles [ 49 , 50 , 51 , 52 , 53 , 54 , 55 ]. These nanoparticles are biodegradable, sub-microscopic liposomes constructed from phospholipids, cholesterol and glycolipids of which α-gal glycolipids are the majority.…”