Improving the efficacy of anti-SSEA4 antibody in pancreatic cancer immunotherapy with glyco- optimization and immune checkpoint blockade

• 成果类型: Article
• 署名作者: Chuang, Po-Kai; Chung, Cinya; Liao, Kuo-Shiang; Wong, Chi-Huey
• 署名单位: Scripps Research Institute; National Sun Yat Sen University; Kaohsiung Medical University; Kaohsiung Medical University Hospital; Academia Sinica - Taiwan
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8425
• DOI: 10.1073/pnas.2517415122
• 发表日期: 2025-09-23
• 关键词: marginal zone; t-cells; receptors; antigens; innate

摘要

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 gamma RIIIA and Fc gamma RIIA 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 gamma RIIA-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.