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
  • 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.

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