BCL-XL-targeting antibody-drug conjugates are active in preclinical models and mitigate on-mechanism toxicity of small-molecule inhibitors
- Sci Adv. 2024 Oct 4;10(40):eado7120. doi: 10.1126/sciadv.ado7120.
- 1. AbbVie Inc., 1 N. Waukegan Road, North Chicago, IL 60064, USA.
Overexpression of the antiapoptotic protein B-cell lymphoma-extra large (BCL-XL) 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-XL inhibitors. Although efficacious in preclinical models, we report herein that selective BCL-XL inhibitors cause severe mechanism-based cardiovascular toxicity in higher preclinical species. To overcome this liability, antibody-drug conjugates were constructed using altered BCL-XL-targeting warheads, unique linker technologies, and therapeutic antibodies. The epidermal growth factor receptor-targeting 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-XL-mediated 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-XL-targeting agent to enter human clinical trials.
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Cat. No.Product NameDescriptionTargetResearch Area
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target: Bcl-2 FamilyResearch Areas: Cancer