1. Academic Validation
  2. BCL-XL-targeting antibody-drug conjugates are active in preclinical models and mitigate on-mechanism toxicity of small-molecule inhibitors

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.
Andrew S Judd 1 Bhupinder Bawa 1 Wayne R Buck 1 Zhi-Fu Tao 1 Yingchun Li 1 Michael J Mitten 1 Milan Bruncko 1 Nathaniel Catron 1 George Doherty 1 Kenneth R Durbin 1 Brian Enright 1 Robin Frey 1 Deanna Haasch 1 Sandra Haman 1 Anthony R Haight 1 Tracy A Henriques 1 James Holms 1 Kamel Izeradjene 1 Russell A Judge 1 Gary J Jenkins 1 Aaron Kunzer 1 Joel D Leverson 1 Ruth L Martin 1 Diya Mitra 1 Scott Mittelstadt 1 Lorne Nelson 1 Paul Nimmer 1 Joann Palma 1 Richard Peterson 1 Darren C Phillips 1 Sherry L Ralston 1 Saul H Rosenberg 1 Xiaoqiang Shen 1 Xiaohong Song 1 Kedar R Vaidya 1 Xilu Wang 1 Jin Wang 1 Yu Xiao 1 Haichao Zhang 1 Xinxin Zhang 1 Eric A Blomme 1 Erwin R Boghaert 1 John C Kalvass 1 Andrew Phillips 1 Andrew J Souers 1
Affiliations

Affiliation

  • 1 AbbVie Inc., 1 N. Waukegan Road, North Chicago, IL 60064, USA.
Abstract

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.

Figures
Products