Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients

作者：Junichiro Yuda, Christine Will, Darren C. Phillips, Linu Abraham, Cory Alvey, Abraham Avigdor, Wayne R. Buck, Lauren M. Besenhofer, Erwin R. Boghaert, Dong Cheng, Dan Cojocari, Kelly Doyle, Terkel Hansen, Kevin Y. Huang, Eric F. Johnson, Andrew S. Judd, Russell A. Judge, J. Cory Kalvass, Aaron Kunzer, Lloyd T. Lam, Rachel Li, Ruth L. Martin, Anthony Mastracchio, Mike Mitten, Adam M. Petrich, Jin Wang, James E. Ward, Haichao Zhang, Xilu Wang, Johannes Wolff, Katherine M. Bell‐McGuinn, Andrew J. Souers · 发表于：Communications Medicine · 年份：2023 · DOI：10.1038/s43856-023-00380-z · 被引用次数：72 · 研究领域：Multiple Myeloma Research and Treatments、Cell death mechanisms and regulation、Ubiquitin and proteasome pathways

BACKGROUND: MCL-1 is a prosurvival B-cell lymphoma 2 family protein that plays a critical role in tumor maintenance and survival and can act as a resistance factor to multiple anticancer therapies. Herein, we describe the generation and characterization of the highly potent and selective MCL-1 inhibitor ABBV-467 and present findings from a first-in-human trial that included patients with relapsed/refractory multiple myeloma (NCT04178902). METHODS: Binding of ABBV-467 to human MCL-1 was assessed in multiple cell lines. The ability of ABBV-467 to induce tumor growth inhibition was investigated in xenograft models of human multiple myeloma and acute myelogenous leukemia. The first-in-human study was a multicenter, open-label, dose-escalation study assessing safety, pharmacokinetics, and efficacy of ABBV-467 monotherapy. RESULTS: Here we show that administration of ABBV-467 to MCL-1-dependent tumor cell lines triggers rapid and mechanism-based apoptosis. In vivo, intermittent dosing of ABBV-467 as monotherapy or in combination with venetoclax inhibits the growth of xenografts from human hematologic cancers. Results from a clinical trial evaluating ABBV-467 in patients with multiple myeloma based on these preclinical data indicate that treatment with ABBV-467 can result in disease control (seen in 1 patient), but may also cause increases in cardiac troponin levels in the plasma in some patients (seen in 4 of 8 patients), without other corresponding cardiac findings. CONCLUSIONS: T...