{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:11:41Z","timestamp":1790266301259,"version":"4.1.0"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2020,2,20]],"date-time":"2020-02-20T00:00:00Z","timestamp":1582156800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Transforming growth factor \u03b2 (TGF\u03b2) signaling has been recently shown to reduce antitumor response to PD-L1 blockade, leading to a renewed enthusiasm in developing anti-TGF\u03b2 therapies for potential combination with cancer immunotherapy agents. Inhibition of TGF\u03b2 signaling in nonclinical toxicology species is associated with serious adverse toxicities including cardiac valvulopathies and anemia. Previously, cardiovascular toxicities have been thought to be limited to small molecule inhibitors of TGF\u03b2 receptor and not considered to be a liability associated with pan-TGF\u03b2 neutralizing monoclonal antibodies (mAbs). Here, we report the toxicity findings associated with a potent pan-TGF\u03b2 neutralizing mAb (pan-TGF\u03b2 mAb; neutralizes TGF\u03b21, 2, and 3) after 5 weekly intravenous doses of 10, 30, and 100\u2009mg\/kg, followed by a 4-week recovery period, in mice and cynomolgus monkeys. Mortality was observed due to acute bleeding and cardiovascular toxicity in mice at \u2265 30\u2009mg\/kg and prolonged menstruation in female monkeys at 100\u2009mg\/kg. Additional findings considered to be on-target exaggerated pharmacology included generalized bleeding and cardiovascular toxicity in mice and monkeys; histopathologic changes in the teeth, tongue, and skin in mice; and abnormal wound healing and microscopic pathology in the bone in monkeys. Importantly, our data indicate that the cardiovascular toxicities associated with the inhibition of TGF\u03b2 signaling are not limited to small molecule inhibitors but are also observed following administration of a potent pan-TGF\u03b2 inhibiting mAb.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaa024","type":"journal-article","created":{"date-parts":[[2020,2,15]],"date-time":"2020-02-15T07:12:55Z","timestamp":1581750775000},"page":"24-34","source":"Crossref","is-referenced-by-count":104,"title":["A Potent Pan-TGF\u03b2 Neutralizing Monoclonal Antibody Elicits Cardiovascular Toxicity in Mice and Cynomolgus Monkeys"],"prefix":"10.1093","volume":"175","author":[{"given":"Mayur S","family":"Mitra","sequence":"first","affiliation":[{"name":"Genentech Inc, South San Francisco, California 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karla","family":"Lancaster","sequence":"first","affiliation":[{"name":"Genentech Inc, South San Francisco, California 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5153-1990","authenticated-orcid":false,"given":"Adeyemi O","family":"Adedeji","sequence":"first","affiliation":[{"name":"Genentech Inc, South San Francisco, California 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gopinath S","family":"Palanisamy","sequence":"first","affiliation":[{"name":"Genentech Inc, South San Francisco, California 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rutwij A","family":"Dave","sequence":"first","affiliation":[{"name":"Genentech Inc, South San Francisco, California 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Zhong","sequence":"first","affiliation":[{"name":"Genentech Inc, South San Francisco, California 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew S","family":"Holdren","sequence":"first","affiliation":[{"name":"Genentech Inc, South San Francisco, California 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon J","family":"Turley","sequence":"first","affiliation":[{"name":"Genentech Inc, South San Francisco, California 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Ching","family":"Liang","sequence":"first","affiliation":[{"name":"Genentech Inc, South San Francisco, California 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wu","sequence":"first","affiliation":[{"name":"Genentech Inc, South San Francisco, California 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y Gloria","family":"Meng","sequence":"first","affiliation":[{"name":"Genentech Inc, South San Francisco, California 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Michel","family":"Vernes","sequence":"first","affiliation":[{"name":"Genentech Inc, South San Francisco, California 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa M","family":"Schutten","sequence":"first","affiliation":[{"name":"Genentech Inc, South San Francisco, California 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,2,20]]},"reference":[{"key":"2020050414175034500_kfaa024-B1","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1177\/0192623311416259","article-title":"Induction of heart valve lesions by small-molecule ALK5 inhibitors","volume":"39","author":"Anderton","year":"2011","journal-title":"Toxicol. 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