2. Academic Validation
  3. Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients

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

  • Commun Med (Lond). 2023 Oct 25;3(1):154. doi: 10.1038/s43856-023-00380-z.
Junichiro Yuda 1,  Christine Will 2,  Darren C Phillips 2,  Linu Abraham 2,  Cory Alvey 2,  Abraham Avigdor 3 4,  Wayne Buck 2,  Lauren Besenhofer 2,  Erwin Boghaert 2 5,  Dong Cheng 2,  Dan Cojocari 2,  Kelly Doyle 2,  T Matthew Hansen 2,  Kevin Huang 2,  Eric F Johnson 2,  Andrew S Judd 2,  Russell A Judge 2,  John C Kalvass 2,  Aaron Kunzer 2,  Lloyd T Lam 2,  Rachel Li 2,  Ruth L Martin 2,  Anthony Mastracchio 2,  Mike Mitten 2 6,  Adam Petrich 2 7 8,  Jin Wang 2,  James E Ward 2 9,  Haichao Zhang 2,  Xilu Wang 2,  Johannes E Wolff 2 10,  Katherine M Bell-McGuinn 2 11,  Andrew J Souers 12
Affiliations

Affiliations

  • 1 National Cancer Center Hospital East, Kashiwa, Japan.
  • 2 AbbVie Inc, North Chicago, IL, USA.
  • 3 Institute of Hematology, Sheba Medical Center, Ramat Gan, Israel.
  • 4 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 5 , Pleasant Prairie, WI, USA.
  • 6 , Beach Park, IL, USA.
  • 7 Northwestern University, Chicago, IL, USA.
  • 8 Daiichi Sankyo, Basking Ridge, NJ, USA.
  • 9 Seagen Inc., Bothell, WA, USA.
  • 10 Replimmune, Puyallop, WA, USA.
  • 11 , Zionsville, IN, USA.
  • 12 AbbVie Inc, North Chicago, IL, USA. andrew.souers@abbvie.com.
PMID: 37880389 DOI: 10.1038/s43856-023-00380-z
Abstract

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: The selectivity of ABBV-467 suggests that treatment-induced troponin release is a consequence of Mcl-1 inhibition and therefore may represent a class effect of Mcl-1 inhibitors in human patients.

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