American Association for Cancer Research
15357163mct200116-sup-237567_2_video_6391027_qcpkzz.mp4 (12.38 MB)

Video D from Preclinical Development of MGC018, a Duocarmycin-based Antibody–drug Conjugate Targeting B7-H3 for Solid Cancer

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posted on 2023-04-03, 18:03 authored by Juniper A. Scribner, Jennifer G. Brown, Thomas Son, Michael Chiechi, Pam Li, Sharad Sharma, Hua Li, Anushka De Costa, Ying Li, Yan Chen, Ann Easton, Nicholas C. Yee-Toy, Francine Z. Chen, Sergey Gorlatov, Bhaswati Barat, Ling Huang, Christina R. Wolff, Jeff Hooley, Tim E. Hotaling, Timur Gaynutdinov, Valentina Ciccarone, James Tamura, Scott Koenig, Paul A. Moore, Ezio Bonvini, Deryk Loo

5000 Hs700T B7-H3 KO/RFP cells alone in the presence of 6.7 nM MGC018



B7-H3, also referred to as CD276, is a member of the B7 family of immune regulatory proteins. B7-H3 is overexpressed on many solid cancers, including prostate cancer, renal cell carcinoma, melanoma, squamous cell carcinoma of the head and neck, non–small cell lung cancer, and breast cancer. Overexpression of B7-H3 is associated with disease severity, risk of recurrence and reduced survival. In this article, we report the preclinical development of MGC018, an antibody–drug conjugate targeted against B7-H3. MGC018 is comprised of the cleavable linker-duocarmycin payload, valine-citrulline-seco duocarmycin hydroxybenzamide azaindole (vc-seco-DUBA), conjugated to an anti-B7-H3 humanized IgG1/kappa mAb through reduced interchain disulfides, with an average drug-to-antibody ratio of approximately 2.7. MGC018 exhibited cytotoxicity toward B7-H3–positive human tumor cell lines, and exhibited bystander killing of target-negative tumor cells when cocultured with B7-H3–positive tumor cells. MGC018 displayed potent antitumor activity in preclinical tumor models of breast, ovarian, and lung cancer, as well as melanoma. In addition, antitumor activity was observed toward patient-derived xenograft models of breast, prostate, and head and neck cancer displaying heterogeneous expression of B7-H3. Importantly, MGC018 exhibited a favorable pharmacokinetic and safety profile in cynomolgus monkeys following repeat-dose administration. The antitumor activity observed preclinically with MGC018, together with the positive safety profile, provides evidence of a potentially favorable therapeutic index and supports the continued development of MGC018 for the treatment of solid cancers.

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