BCL-X-targeting antibody-drug conjugates are active in preclinical models and mitigate on-mechanism toxicity of small-molecule inhibitors.

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

TLDR

  • The study investigates the use of a protein called BCL-X as a target for cancer treatment. The study finds that selective small-molecule BCL-X inhibitors cause severe cardiovascular toxicity in higher preclinical species. The study constructs antibody-drug conjugates to overcome this toxicity and finds that the epidermal growth factor receptor-targeting antibody-drug conjugate AM1-15 is safe and effective in monkeys. The study also uncovers an unexpected toxicity in monkey kidneys upon repeat dosing of AM1-15, which is mitigated via further drug-linker modification. The study suggests that antibody-drug conjugates can be a safer and more effective way to target BCL-X in cancer treatment.

Abstract

Overexpression of the antiapoptotic protein B-cell lymphoma-extra large (BCL-X) 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-Xinhibitors. Although efficacious in preclinical models, we report herein that selective BCL-Xinhibitors cause severe mechanism-based cardiovascular toxicity in higher preclinical species. To overcome this liability, antibody-drug conjugates were constructed using altered BCL-X-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-X-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-X-targeting agent to enter human clinical trials.

Overview

  • The study investigates the association of overexpression of the antiapoptotic protein B-cell lymphoma-extra large (BCL-X) with drug resistance and disease progression in various cancers. The study aims to develop selective small-molecule BCL-X inhibitors as a therapeutic target. The study reports that selective BCL-X inhibitors cause severe mechanism-based cardiovascular toxicity in higher preclinical species. The study constructs antibody-drug conjugates using altered BCL-X-targeting warheads, unique linker technologies, and therapeutic antibodies to overcome the cardiovascular toxicity of selective BCL-X inhibitors. The study finds that the epidermal growth factor receptor-targeting antibody-drug conjugate AM1-15 inhibits tumor xenograft growth and does not cause cardiovascular toxicity or dose-limiting thrombocytopenia in monkeys. The study uncovers an unprecedented BCL-X-mediated toxicity in monkey kidneys upon repeat dosing of AM1-15, which is 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-X-targeting agent to enter human clinical trials.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions, specifically the use of selective small-molecule BCL-X inhibitors versus antibody-drug conjugates. The study identifies severe mechanism-based cardiovascular toxicity as a significant difference between the two interventions in higher preclinical species. The study finds that the epidermal growth factor receptor-targeting antibody-drug conjugate AM1-15 inhibits tumor xenograft growth and does not cause cardiovascular toxicity or dose-limiting thrombocytopenia in monkeys, while an unprecedented BCL-X-mediated toxicity is uncovered in monkey kidneys upon repeat dosing of AM1-15. The study suggests that further drug-linker modification can mitigate the toxicity of AM1-15 and afford AM1-AAA (AM1-25), which has since been incorporated into mirzotamab clezutoclax, the first selective BCL-X-targeting agent to enter human clinical trials.

Implications and Future Directions

  • The study's findings highlight the potential cardiovascular toxicity of selective BCL-X inhibitors in higher preclinical species, which may limit their use as therapeutic agents. The study suggests that antibody-drug conjugates can overcome this toxicity by targeting BCL-X in a more specific and controlled manner. The study identifies an unprecedented BCL-X-mediated toxicity in monkey kidneys upon repeat dosing of AM1-15, which can be mitigated via further drug-linker modification. The study suggests that the AAA drug-linker can be incorporated into future antibody-drug conjugates to improve their safety and efficacy. The study also highlights the potential of selective BCL-X-targeting agents, such as mirzotamab clezutoclax, for human clinical trials.
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