{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T18:19:24Z","timestamp":1781288364564,"version":"3.54.1"},"reference-count":87,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T00:00:00Z","timestamp":1762473600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    HER2 is a well-established oncogenic driver in breast, gastric, and other solid tumors. While HER2-targeted therapies such as trastuzumab and pertuzumab have improved clinical outcomes, resistance, particularly to trastuzumab, remains a major therapeutic challenge. Here, we engineered two IgG-VHH biparatopic antibodies (bpAbs), A9B5-Bs-5 and A9B5-Bs-7, incorporating an ECD I-binding nanobody A9B5 with the IgG scaffolds. These bpAbs target non-overlapping epitopes on the HER2 extracellular domain, promoting rapid receptor internalization and demonstrating superior antitumor activity compared to the trastuzumab and pertuzumab combination in trastuzumab-resistant tumor cells. Structural modeling suggests that both bpAbs engage HER2 in a\n                    <jats:italic>trans<\/jats:italic>\n                    -binding mode, leading to receptor clustering and interference with ligand-driven HER2 heterodimerization. These findings demonstrate that epitope-guided biparatopic antibody design can enhance HER2 downregulation and restore sensitivity to HER2-targeted therapy\n                    <jats:italic>in vitro<\/jats:italic>\n                    , providing a strategy for the development of next-generation receptor-targeted biologics.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2025.1711433","type":"journal-article","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T06:22:07Z","timestamp":1762496527000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Engineering HER2-targeted biparatopic antibodies to promote receptor internalization and restore antitumor efficacy"],"prefix":"10.3389","volume":"16","author":[{"given":"Xinlin","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanpeng","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongming","family":"Xing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiming","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21583","article-title":"Breast 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