{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T06:40:37Z","timestamp":1793256037802,"version":"4.5.0"},"reference-count":38,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T00:00:00Z","timestamp":1687737600000},"content-version":"unspecified","delay-in-days":25,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82072728"],"award-info":[{"award-number":["82072728"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2023,5,21]]},"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Claudin18.2 (CLDN18.2) is a tight junction protein that has been identified as a clinically proven target in gastric cancer. Stimulation of 4-1BB with agonistic antibodies is also a promising strategy for immunotherapy and 4-1BB<jats:sup>+<\/jats:sup> T cells were reported to be present within the tumor microenvironment of patients with gastric cancer. However, hepatotoxicity-mediated by 4-1BB activation was observed in clinical trials of agonistic anti-4-1BB monoclonal antibodies.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>To specifically activate the 4-1BB<jats:sup>+<\/jats:sup> T cells in tumor and avoid the on-target liver toxicity, we developed a novel CLDN18.2\u00d74-1BB bispecific antibody (termed \u2018givastomig\u2019 or \u2018ABL111\u2019; also known as TJ-CD4B or TJ033721) that was designed to activate 4-1BB signaling in a CLDN18.2 engagement-dependent manner.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>4-1BB<jats:sup>+<\/jats:sup> T cells were observed to be coexisted with CLDN18.2<jats:sup>+<\/jats:sup> tumor cells in proximity by multiplex immunohistochemical staining of tumor tissues from patients with gastric cancer (n=60). Givastomig\/ABL111 could bind to cell lines expressing various levels of CLDN18.2 with a high affinity and induce 4-1BB activation in vitro only in the context of CLDN18.2 binding. The magnitude of T-cell activation by givastomig\/ABL111 treatment was closely correlated with the CLDN18.2 expression level of tumor cells from gastric cancer patient-derived xenograft model. Mechanistically, givastomig\/ABL111 treatment could upregulate the expression of a panel of pro-inflammatory and interferon-\u03b3-responsive genes in human peripheral blood mononuclear cells when co-cultured with CLDN18.2<jats:sup>+<\/jats:sup> tumor cells. Furthermore, in humanized 4-1BB transgenic mice inoculated with human CLDN18.2-expressing tumor cells, givastomig\/ABL111 induced a localized immune activation in tumor as evident by the increased ratio of CD8<jats:sup>+<\/jats:sup>\/regulatory T cell, leading to the superior antitumor activity and long-lasting memory response against tumor rechallenge. Givastomig\/ABL111 was well tolerated, with no systemic immune response and hepatotoxicity in monkeys.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Givastomig\/ABL111 is a novel CLDN18.2\u00d74-1BB bispecific antibody which has the potential to treat patients with gastric cancer with a wide range of CLDN18.2 expression level through the restricted activation of 4-1BB<jats:sup>+<\/jats:sup> T cells in tumor microenvironment to avoid the risk of liver toxicity and systemic immune response.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2023-006704","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T12:15:53Z","timestamp":1687781753000},"page":"e006704","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":56,"title":["CLDN18.2 and 4-1BB bispecific antibody givastomig exerts antitumor 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