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Discovery of ABBV-3373, an Anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody Drug Conjugate

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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Med. Chem. 2022, 65, 23, 15893-15934
    ADDITION/CORRECTION This article has been corrected. View the notice.
    Article

    Discovery of ABBV-3373, an Anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody Drug Conjugate
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    • Adrian D. Hobson*
      Adrian D. Hobson
      AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States
      *Email: [email protected]
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      Orcidhttps://orcid.org/0000-0003-3948-0577
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    • Martin E. Hayes
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      WuXi AppTec, 168 Nanhai Road, Tianjin Economic-Technological Development Area TEDA, Tianjin 300457, China
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    • Liang Sun
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      Orcidhttps://orcid.org/0000-0002-5253-3736
    • Qiang Zhang
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      WuXi AppTec, 168 Nanhai Road, Tianjin Economic-Technological Development Area TEDA, Tianjin 300457, China
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    • Axel Hernandez Jr.
      Axel Hernandez, Jr.
      AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States
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      Agnieszka K. Bischoff
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      AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States
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      Orcidhttps://orcid.org/0000-0003-4984-8435
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      AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States
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    Other Access OptionsSupporting Information (2)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2022, 65, 23, 15893–15934
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    https://doi.org/10.1021/acs.jmedchem.2c01579
    Published November 17, 2022
    Copyright © 2022 American Chemical Society
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    Abstract

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    Using a convergent synthetic route to enable multiple points of diversity, a series of glucocorticoid receptor modulators (GRM) were profiled for potency, selectivity, and drug-like properties in vitro. Despite covering a large range of diversity, profiling the nonconjugated small molecule was suboptimal and they were conjugated to a mouse antitumor necrosis factor (TNF) antibody using the MP-Ala-Ala linker. Screening of the resulting antibody drug conjugates (ADCs) provided a better assessment of efficacy and physical properties, reinforcing the need to conduct structure–activity relationship studies on the complete ADC. DAR4 ADCs were screened in an acute mouse contact hypersensitivity model measuring biomarkers to ensure a sufficient therapeutic window. In a chronic mouse arthritis model, mouse anti-TNF GRM ADCs were efficacious after a single dose of 10 mg/kg i.p. for over 30 days. Data on the unconjugated payloads and mouse surrogate anti-TNF ADCs identified payload 17 which was conjugated to a human anti-TNF antibody and advanced to the clinic as ABBV-3373.

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c01579.

    • GR competitive receptor binding assay protocol; GRE luciferase reporter assay protocol; mineralcorticoid receptor cell assay protocol; PR binding assay protocol; AR binding assay protocol; ER binding assay; mouse CHS protocol; mouse collagen-induced arthritis model protocol; plasma P1NP concentration protocol; plasma corticosterone concentration protocol; 1H and 13C NMR spectra for compounds 19, 20, 26, 31, 53, and 72; 19F NMR spectra for compounds 19, 20, 31, and 53; HIC spectra for ADCs 120–135; SEC spectra for ADCs 121 and 122; mass spectral data for ADCs 121 and 122; LCMS methods; HT-ADME data for compounds 5, 6, 8, 15, 17, 19, 20, 24–26, 28, 30–32, 37, 43, 62, 64–66, 69–74, 76, 78, and 79; and X-ray data for compounds 17 and 136 (PDF)

    • Molecular formula strings and associated biochemical data (CSV)

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    Cited By

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    This article is cited by 7 publications.

    1. Nathan B. Bennett, Xiaoqiang Shen, Bradley D. Gates, Dennie S. Welch, Mark A. Servos, Justin A. Simanis, Ryan G. Ellis, Haixiao Qiu, Eric G. Moschetta, Jiajie Feng, Moussa Boukerche, Michael Rasmussen, Laura A. McKee, Laurie B. Mlinar, Shuang Chen, Zhe Wang. Development and Execution of a Scalable Route to an Immunology ADC Drug-Linker for ABBV-154. Organic Process Research & Development 2024, 28 (7) , 2499-2517. https://doi.org/10.1021/acs.oprd.4c00142
    2. Nathan B. Bennett, Laurie B. Mlinar, Eric G. Moschetta, Ryan G. Ellis, Ryan Chung, Onkar Manjrekar, Michael Rasmussen, Laura A. McKee, Mark A. Servos, Justin A. Simanis, Bradley D. Gates, Xiaoqiang Shen, Dennie S. Welch, Zhe Wang. Use of Impinging Jet to Improve Scalability in the Preparation of the ABBV-154 Drug-Linker. Organic Process Research & Development 2024, 28 (7) , 2518-2533. https://doi.org/10.1021/acs.oprd.4c00143
    3. Nathan B. Bennett, Bradley D. Gates, Justin A. Simanis, James W. Treadway, Steven M. Richter, Dennie S. Welch. Development of a Scalable Synthesis of a Drug-Linker for ABBV-3373. Organic Process Research & Development 2024, 28 (6) , 2237-2246. https://doi.org/10.1021/acs.oprd.3c00447
    4. Christopher C. Marvin, Adrian D. Hobson, Michael J. McPherson, Martin E. Hayes, Meena V. Patel, Diana L. Schmidt, Tongmei Li, John T. Randolph, Agnieszka K. Bischoff, Julia Fitzgibbons, Lu Wang, Lu Wang, Axel Hernandez, Jr, Ying Jia, Christian A. Goess, Shaughn H. Bryant, Suzanne L. Mathieu, Jianwen Xu. Anti-TNF Thioester Glucocorticoid Antibody–Drug Conjugate Fully Inhibits Inflammation with Minimal Effect on Systemic Corticosterone Levels in a Mouse Arthritis Model. Journal of Medicinal Chemistry 2024, 67 (11) , 9495-9515. https://doi.org/10.1021/acs.jmedchem.4c00598
    5. Christopher C. Marvin, Adrian D. Hobson, Michael McPherson, Theresa A. Dunstan, Thomas R. Vargo, Martin E. Hayes, Margaret M. Fettis, Agnieszka Bischoff, Lu Wang, Lu Wang, Axel Hernandez, Jr., Ying Jia, Jason Z. Oh, Yu Tian. Self-Immolative Carbamate Linkers for CD19-Budesonide Antibody–Drug Conjugates. Bioconjugate Chemistry 2023, 34 (10) , 1835-1850. https://doi.org/10.1021/acs.bioconjchem.3c00354
    6. Adrian D. Hobson, Jianwen Xu, Dennie S. Welch, Christopher C. Marvin, Michael J. McPherson, Bradley Gates, Xiaoli Liao, Markus Hollmann, Michael J. Gattner, Kristina Dzeyk, Hetal Sarvaiya, Vikram M. Shenoy, Margaret M. Fettis, Agnieszka K. Bischoff, Lu Wang, Ling C. Santora, Lu Wang, Julia Fitzgibbons, Paulin Salomon, Axel Hernandez, Jr., Ying Jia, Christian A. Goess, Suzanne L. Mathieu, Shaughn H. Bryant, Mary E. Larsen, Baoliang Cui, Yu Tian. Discovery of ABBV-154, an anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody-Drug Conjugate (iADC). Journal of Medicinal Chemistry 2023, 66 (17) , 12544-12558. https://doi.org/10.1021/acs.jmedchem.3c01174
    7. Adrian D. Hobson, Jianwen Xu, Christopher C. Marvin, Michael J. McPherson, Markus Hollmann, Michael Gattner, Kristina Dzeyk, Margaret M. Fettis, Agnieszka K. Bischoff, Lu Wang, Julia Fitzgibbons, Lu Wang, Paulin Salomon, Axel Hernandez, Jr., Ying Jia, Hetal Sarvaiya, Christian A. Goess, Suzanne L. Mathieu, Ling C. Santora. Optimization of Drug-Linker to Enable Long-term Storage of Antibody–Drug Conjugate for Subcutaneous Dosing. Journal of Medicinal Chemistry 2023, 66 (13) , 9161-9173. https://doi.org/10.1021/acs.jmedchem.3c00794
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2022, 65, 23, 15893–15934
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.2c01579
    Published November 17, 2022
    Copyright © 2022 American Chemical Society
    Request reuse permissions

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