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
  • 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. [email protected].
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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