BCL-X_L-targeting antibody-drug conjugates are active in preclinical models and mitigate on-mechanism toxicity of small-molecule inhibitors.

ABSTRACT: Overexpression of the antiapoptotic protein B-cell lymphoma-extra large (BCL-X_L) 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_L inhibitors. Although efficacious in preclinical models, we report herein that selective BCL-X_L inhibitors cause severe mechanism-based cardiovascular toxicity in higher preclinical species. To overcome this liability, antibody-drug conjugates were constructed using altered BCL-X_L-targeting warheads, unique linker technologies, and therapeutic antibodies. The epidermal growth factor receptor-targeting antibody-drug conjugate AM1-15 inhibited growth of tumor xenografts a

SUBMITTER: Judd AS 

PROVIDER: S-EPMC11451551 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature