{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T17:59:45Z","timestamp":1773770385628,"version":"3.50.1"},"reference-count":132,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:00:00Z","timestamp":1773705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The \u03b1-gal epitope is synthesized in non-primate mammals and New-World monkeys by the glycosylation enzyme \u03b11,3galactosyltransferase (\u03b11,3GT), encoded by the GGTA1 gene. Ancestral Old-World monkeys and apes synthesizing \u03b1-gal epitopes underwent extinction 20\u201330 million years ago. Their mutated offspring, with the inactivated GGTA1 gene, survived and produced the natural anti-Gal antibody, specifically binding \u03b1-gal epitopes. Anti-Gal protected the surviving offspring from lethal viruses presenting \u03b1-gal epitopes, which killed \u03b1-gal-synthesizing parental primates. Anti-Gal constitutes ~1% of human immunoglobulins and is also produced in Old-World monkeys and apes. \u03b1-Gal epitopes can serve as therapeutic agents in several clinical disciplines: 1. Cancer immunotherapy: Engineering cancer cells to express \u03b1-gal epitopes results in anti-Gal binding to these cells and localized activation of the complement system that kills these cancer cells and recruits the antigen-presenting cells (APCs) dendritic cells and macrophages. Anti-Gal bound to cancer cells targets them for robust uptake by APCs, which process internalized tumor antigens (TAs) and transport them to lymph nodes for activation of cytotoxic T-cells. These T-cells kill TA-presenting metastatic tumor cells. Clinical trials demonstrated that such engineering is achieved by intra-tumoral injection of \u03b1-gal glycolipids, the use of recombinant \u03b11,3GT, or the use of oncolytic viruses containing the GGTA1 gene. 2. Viral vaccines: Inactivated whole-virus vaccines presenting \u03b1-gal epitopes bind anti-Gal, which targets them for extensive uptake by APCs, thereby increasing their immunogenicity by ~100-fold. 3. Injured-tissue regeneration: Anti-Gal binding to \u03b1-gal-presenting nanoparticles administered to wounds, into the post-myocardial infarction (MI) injured myocardium and into injured spinal cord, activates the complement system that recruits pro-regenerative macrophages, which orchestrate regeneration by recruiting stem cells and the secretion of pro-regenerative cytokines. All these findings suggest that \u03b1-gal\/anti-Gal antibody interaction can serve as a novel therapeutic approach, applicable to various clinical settings.<\/jats:p>","DOI":"10.3390\/ijms27062737","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T14:50:48Z","timestamp":1773759048000},"page":"2737","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The \u03b1-Gal Epitope (Gal\u03b11-3Gal\u03b21-4GlcNAc) as Therapeutic Agent in Cancer Immunotherapy, Vaccine Effectiveness Amplification and Injured Tissue Regeneration"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4264-8801","authenticated-orcid":false,"given":"Uri","family":"Galili","sequence":"first","affiliation":[{"name":"Department of Medicine, Rush University Medical Center, Chicago, IL 60612, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1073\/pnas.84.5.1369","article-title":"Evolutionary relationship between the anti-Gal antibody and the Gal\u03b11-3Gal epitope in primates","volume":"84","author":"Galili","year":"1987","journal-title":"Proc. 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