{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T04:09:02Z","timestamp":1791950942053,"version":"4.3.4"},"reference-count":60,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"40","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2024,10,4]]},"abstract":"<jats:p>\n                    Overexpression of the antiapoptotic protein B-cell lymphoma-extra large (BCL-X\n                    <jats:sub>L<\/jats:sub>\n                    ) is associated with drug resistance and disease progression in numerous cancers. The compelling nature of this protein as a therapeutic target prompted efforts to develop selective small-molecule BCL-X\n                    <jats:sub>L<\/jats:sub>\n                    inhibitors. Although efficacious in preclinical models, we report herein that selective BCL-X\n                    <jats:sub>L<\/jats:sub>\n                    inhibitors cause severe mechanism-based cardiovascular toxicity in higher preclinical species. To overcome this liability, antibody-drug conjugates were constructed using altered BCL-X\n                    <jats:sub>L<\/jats:sub>\n                    \u2013targeting warheads, unique linker technologies, and therapeutic antibodies. The epidermal growth factor receptor\u2013targeting antibody-drug conjugate AM1-15 inhibited growth of tumor xenografts and did not cause cardiovascular toxicity nor dose-limiting thrombocytopenia in monkeys. While an unprecedented BCL-X\n                    <jats:sub>L<\/jats:sub>\n                    \u2013mediated toxicity was uncovered in monkey kidneys upon repeat dosing of AM1-15, this toxicity was mitigated via further drug-linker modification to afford AM1-AAA (AM1-25). The AAA drug-linker has since been incorporated into mirzotamab clezutoclax, the first selective BCL-X\n                    <jats:sub>L<\/jats:sub>\n                    \u2013targeting agent to enter human clinical trials.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.ado7120","type":"journal-article","created":{"date-parts":[[2024,10,4]],"date-time":"2024-10-04T13:58:42Z","timestamp":1728050322000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":27,"title":["BCL-X\n                    <sub>L<\/sub>\n                    \u2013targeting antibody-drug conjugates are active in preclinical models and mitigate on-mechanism toxicity of small-molecule inhibitors"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2562-8841","authenticated-orcid":true,"given":"Andrew S.","family":"Judd","sequence":"first","affiliation":[{"name":"AbbVie Inc., 1 N. 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