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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