{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T07:28:08Z","timestamp":1792481288707,"version":"4.5.0"},"reference-count":49,"publisher":"National Academy of Sciences","issue":"38","license":[{"start":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T00:00:00Z","timestamp":1757894400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100022281","name":"AS | Genomics Research Center, Academia Sinica","doi-asserted-by":"publisher","award":["Summit Program"],"award-info":[{"award-number":["Summit Program"]}],"id":[{"id":"10.13039\/501100022281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["AI130227"],"award-info":[{"award-number":["AI130227"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,9,23]]},"abstract":"<jats:p>Pancreatic cancer remains one of the most lethal malignancies with limited therapeutic options. Among the alternative targets explored for pancreatic cancer, the glycolipid stage-specific embryonic antigen-4 (SSEA4) has been extensively studied. We have previously demonstrated that the chimeric anti-SSEA4 antibody with alpha-2,6-sialylated complex type biantennary glycan (SCT) or its 3-fluorosialyl derivative (FSCT) attached to the Fc-Asn297 residue exhibited enhanced binding to the Fc-receptors Fc\u03b3RIIIA and Fc\u03b3RIIA which are responsible for antibody-dependent cellular cytotoxicity and phagocytosis as well as vaccinal effect. Here, we found that high-SSEA4 expression correlates with increasing tumor proliferation and sensitivity to the glyco-optimized antibodies (anti-SSEA4-SCT and anti-SSEA4-FSCT) which preferentially recruit NKG2D-expressing natural killer cells and Fc\u03b3RIIA-bearing macrophages with enhanced target killing activity. We also uncovered an immune evasion mechanism involving the interaction of sialoglycans on the cancer cell with Siglec-9 on NK cells or Siglec-10 on macrophages to block the antibody-mediated effector functions, and this immune checkpoint inhibition can be suppressed with the removal of sialic acid on cancer cells or blockade of Siglec recognition. In xenograft models, the glyco-optimized antibodies exhibited superior inhibition of tumor growth with high-SSEA4 expression compared to the wild-type antibody and persistent antitumor activity without additional antibody administration. These findings support anti-SSEA4 antibodies with enhanced effector functions and blockade of Siglec-mediated immune checkpoint as a promising therapeutic strategy for pancreatic cancer.<\/jats:p>","DOI":"10.1073\/pnas.2517415122","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T19:08:34Z","timestamp":1757963314000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":7,"title":["Improving the efficacy of anti-SSEA4 antibody in pancreatic cancer immunotherapy with glyco-optimization and immune checkpoint blockade"],"prefix":"10.1073","volume":"122","author":[{"given":"Po-Kai","family":"Chuang","sequence":"first","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute","place":["La Jolla"]},{"name":"Institute of Biomedical Sciences, National Sun Yat-Sen University","place":["Kaohsiung, Taiwan"]},{"name":"Kaohsiung Medical University Hospital, Kaohsiung Medical 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