{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T14:41:21Z","timestamp":1787496081189,"version":"build-2736575974"},"reference-count":50,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T00:00:00Z","timestamp":1743638400000},"content-version":"unspecified","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Rondo Therapeutics Inc","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,3,16]]},"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>T-cell costimulation is crucial for an effective and sustained antitumor immune response, and inadequate expression of costimulatory ligands within tumors can impair T-cell function. Bispecific antibodies (bsAbs) targeting a tumor-associated antigen and the T-cell costimulatory receptor CD28 represent a novel class of immune-stimulatory therapeutics designed to enhance antitumor immune responses by selectively delivering T-cell costimulation directly to the tumor microenvironment. This approach holds the potential to improve the survival, proliferation, and cytotoxic function of antitumor T cells while minimizing the risk of systemic immune activation. Urothelial cancer (UC) is associated with significant morbidity and mortality worldwide, particularly in advanced disease settings. Nectin-4, a membrane protein highly expressed in UC with limited expression in healthy tissues, presents a compelling target for therapeutic intervention.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Using our proprietary high-throughput antibody discovery pipeline, we identified a panel of novel antibodies with a range of affinities for CD28 and Nectin-4 and successfully engineered them as bsAbs. We tested the T-cell costimulatory function of these molecules\n                      <jats:italic>in vitro<\/jats:italic>\n                      using primary human T cells and human cancer cell lines. Based on these results, we selected a clinical candidate which we assessed in a syngeneic mouse tumor model system and investigated tolerability and pharmacokinetics (PK) in non-human primates (NHP).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our\n                      <jats:italic>in vitro<\/jats:italic>\n                      studies demonstrated that these bsAbs effectively enhance T-cell activation and cytotoxicity against Nectin-4 positive tumor cells in the presence of T-cell receptor engagement. The bsAb panel exhibited a range of potencies, enabling the selection of a clinical candidate, termed RNDO-564, that maximized antitumor efficacy as well as the likelihood of a broad therapeutic window. Tumor-bearing syngeneic mouse models confirmed the\n                      <jats:italic>in vivo<\/jats:italic>\n                      efficacy of RNDO-564, demonstrating significant tumor regression both as a single agent and in combination with an immune checkpoint inhibitor. We observed favorable PK and tolerability profiles in NHP assessments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study reports the first CD28 bsAb targeting Nectin-4 and highlights the potential of CD28 \u00d7 Nectin-4 bsAbs as a new immunotherapeutic modality. The findings support the clinical development of RNDO-564 in patients with locally advanced and metastatic UC and other Nectin-4 positive malignancies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2024-011323","type":"journal-article","created":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T09:42:23Z","timestamp":1743846143000},"page":"e011323","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Potency-optimized CD28-activating bispecific antibody for the targeted treatment of Nectin-4 positive cancers"],"prefix":"10.1136","volume":"13","author":[{"given":"Manpreet","family":"Kaur","sequence":"first","affiliation":[{"name":"Preclinical Biology, Rondo Therapeutics Inc, Hayward, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"R\u00fcger","sequence":"additional","affiliation":[{"name":"Protein Science, Rondo Therapeutics Inc, Hayward, California, 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