{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:56:26Z","timestamp":1792112186897,"version":"4.4.0"},"reference-count":45,"publisher":"BMJ","issue":"12","license":[{"start":{"date-parts":[[2025,12,21]],"date-time":"2025-12-21T00:00:00Z","timestamp":1766275200000},"content-version":"unspecified","delay-in-days":20,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,12,1]]},"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      CCR4\n                      <jats:sup>+<\/jats:sup>\n                      regulatory T cells (Tregs), which are widely present in peripheral circulation and tumor microenvironment (TME), promote tumor immune evasion by infiltrating human epidermal growth factor receptor 2-positive (HER2\n                      <jats:sup>+<\/jats:sup>\n                      ) tumors in a chemokine-driven manner. However, therapies targeting CCR4 (eg, mogamulizumab) for systemic Treg depletion risk significant toxicity and have far been confined to hematological malignancies. Notably, tumor-chemotactic peripheral Tregs\u2014key precursors to tumor-infiltrating Tregs (tumor-infiltrating lymphocyte (TIL)-Tregs)\u2014remain overlooked.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We designed and expressed four candidate anti-HER2\u00d7CCR4 DVD-Ig bispecific antibodies with varying degrees of anti-CCR4 domain masking, while leaving anti-HER2 domains fully exposed, to preferentially deplete tumor-associated Tregs, including TIL-Tregs and tumor-chemotactic peripheral Tregs. Stability and antitumor activity were assessed in vitro. In human immune system-reconstituted NOG mice, we systematically: (1) conducted a comprehensive dose-response evaluation of the XL-11 to characterize pharmacological efficacy and potential systemic toxicity, (2) assessed the immune memory, (3) studied the synergy of XL-11 with programmed cell death protein-1\/programmed death-ligand 1 (PD-1\/L1) blocker, and (4) analyzed pharmacokinetic profile (PK).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The lower affinity for CCR4 compared with HER2 enables anti-HER2\u00d7CCR4 DVD-Igs to priority target TIL-Tregs, and reduce binding to peripheral Tregs compared with mogamulizumab. Anti-HER2\u00d7CCR4 DVD-Igs inhibit Treg chemotaxis to TME, and killing Tregs and HER2\n                      <jats:sup>+<\/jats:sup>\n                      tumor cells through antibody-dependent cellular cytotoxicity. Among the candidates, XL-11, which had the greatest exposure of the anti-CCR4 domain, was selected for in vivo evaluation due to its superior stability and potent antitumor activity. In vivo models of gastric cancer and breast cancer, XL-11, by reducing TIL-Tregs and increasing CD8\n                      <jats:sup>+<\/jats:sup>\n                      \/Tregs ratios, induces potent antitumor activity even in advanced stages, with no evidence of metastasis. Concurrently, XL-11 specifically depletes tumor-chemotactic peripheral Tregs, further enhancing antitumor immunity while avoiding reducing Tregs throughout the body even at a high dose (10\u2009mg\/kg). There was no increase in memory T cells. In addition, XL-11 enhances the antitumor activity of anti-PD-1 antibodies and shows superior PK properties.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      XL-11 mediates potent antitumor immunity in advanced HER2\n                      <jats:sup>+<\/jats:sup>\n                      tumors while avoiding reducing Tregs throughout the body. XL-11 also acts synergistically with anti-PD-1 therapy, and exhibits favorable stability and PK supporting clinical translation. This work advances Treg-targeted therapies in HER2\n                      <jats:sup>+<\/jats:sup>\n                      tumors and overcomes the therapeutic limitations of mogamulizumab.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-012829","type":"journal-article","created":{"date-parts":[[2025,12,21]],"date-time":"2025-12-21T19:10:12Z","timestamp":1766344212000},"page":"e012829","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Anti-HER2\u00d7CCR4 bispecific antibody enhances antitumor immunity in advanced HER2-positive tumors by chemotaxis blockade and depletion of tumor-associated Tregs, without inducing systemic toxicity"],"prefix":"10.1136","volume":"13","author":[{"given":"Chaokun","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, 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