{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T11:30:49Z","timestamp":1791545449500,"version":"4.3.4"},"reference-count":50,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T00:00:00Z","timestamp":1767916800000},"content-version":"unspecified","delay-in-days":8,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010795","name":"Chugai Pharmaceutical","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100010795","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,12,17]]},"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Intratumoral regulatory T cells (Tregs) are associated with diminished antitumor immunity and poor prognosis in many cancers, with tumor-infiltrating effector Tregs expressing high levels of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). While Treg depletion is a promising strategy for cancer immunotherapy, systemic Treg depletion may lead to severe autoimmune toxicity. Therefore, to selectively deplete intratumoral Tregs, we used extracellular ATP (exATP), which is highly elevated in solid tumors, as a tumor-selective small molecule.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We generated ROSE12, a novel anti-CTLA-4 Fc gamma receptors (Fc\u03b3Rs)-binding-enhanced-Fc exATP-dependent switch antibody that reduces Tregs only in the presence of exATP. We evaluated ATP-dependent binding affinity, antibody-dependent cellular cytotoxicity (ADCC) activity in vitro, and antitumor efficacy of monotherapy and combination therapy with anti-programmed death-ligand 1 (PD-L1) in CTLA-4\/CD3 double humanized mouse models. Safety profiles were assessed in cynomolgus monkeys.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      ROSE12 demonstrated ATP concentration-dependent binding to CTLA-4, with strong binding at 100\u2009\u00b5mol\/L but no binding without ATP. ROSE12 demonstrated stronger exATP-dependent ADCC activity in vitro and preferentially reduced CTLA-4\n                      <jats:sup>+<\/jats:sup>\n                      Tregs over activated conventional T cells. The engineered asymmetric re-engineering technology-Fc (ART-Fc) region, a proprietary Fc engineering technology, showed enhanced binding to activating Fc\u03b3RIIa and Fc\u03b3RIIIa while reducing binding to inhibitory Fc\u03b3RIIb. In mouse models, ROSE12 monotherapy significantly inhibited tumor growth in both conventional and PD-L1 therapy-resistant tumors by reducing intratumoral Tregs and increasing CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell infiltration. Combination therapy with anti-PD-L1 showed synergistic antitumor efficacy with enhanced intratumoral CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell activation without increasing systemic immune activation. Unlike Fc\u03b3Rs binding-enhanced conventional anti-CTLA-4, ROSE12 did not induce systemic immune activation or colitis symptoms, demonstrating a 30\u2013300-fold wider therapeutic window. The tumor-selective mechanism was confirmed in humanized mouse models, where ROSE12 reduced only intratumoral Tregs while sparing splenic Tregs. In cynomolgus monkeys, ROSE12 was well tolerated even at 30\u2009mg\/kg\/week compared with the 3\u201310\u2009mg\/kg\/week limits for conventional anti-CTLA-4 antibodies such as non-fucosylated ipilimumab and ipilimumab.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These findings support the clinical development of ROSE12 as a tumor-selective Treg-depleting immunotherapy with potential efficacy in programmed cell death protein-1\/PD-L1 therapy-resistant patients. The favorable safety profile was attributed to the ATP-dependent binding mechanism that restricts activity to the high-ATP tumor microenvironment. ROSE12 is currently being evaluated in phase I clinical trials (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05907980\">NCT05907980<\/jats:ext-link>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-013397","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T14:40:43Z","timestamp":1767969643000},"page":"e013397","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["ROSE12, a novel anti-CTLA-4 Fc\u03b3Rs binding-enhanced antibody activated by extracellular adenosine triphosphate, shows tumor-selective regulatory T-cell depletion and antitumor efficacy without systemic immune activation"],"prefix":"10.1136","volume":"14","clinical-trial-number":[{"clinical-trial-number":"nct05907980","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05907980","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05907980","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0894-6102","authenticated-orcid":false,"given":"Hiroki","family":"Hayashi","sequence":"first","affiliation":[{"name":"Chugai Pharmaceutical Co., Ltd., Research Div, Yokohama, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanako","family":"Tatsumi","sequence":"additional","affiliation":[{"name":"Chugai Pharmaceutical Co., Ltd., Research Div, Yokohama, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Katada","sequence":"additional","affiliation":[{"name":"Chugai Pharmaceutical Co., Ltd., Research Div, Yokohama, Kanagawa, 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