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Anti-TNF Thioester Glucocorticoid Antibody–Drug Conjugate Fully Inhibits Inflammation with Minimal Effect on Systemic Corticosterone Levels in a Mouse Arthritis Model

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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Med. Chem. 2024, 67, 11, 9495-9515
    Article

    Anti-TNF Thioester Glucocorticoid Antibody–Drug Conjugate Fully Inhibits Inflammation with Minimal Effect on Systemic Corticosterone Levels in a Mouse Arthritis Model
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    • Christopher C. Marvin*
      Christopher C. Marvin
      AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States
      *Email: [email protected]
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      Orcidhttps://orcid.org/0000-0003-4984-8435
    • Adrian D. Hobson
      Adrian D. Hobson
      AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States
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      Orcidhttps://orcid.org/0000-0003-3948-0577
    • Michael J. McPherson
      Michael J. McPherson
      AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States
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    • Martin E. Hayes
      Martin E. Hayes
      AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States
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    • Meena V. Patel
      Meena V. Patel
      AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States
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      Orcidhttps://orcid.org/0000-0003-2068-6954
    • Diana L. Schmidt
      Diana L. Schmidt
      AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States
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    • Tongmei Li
      Tongmei Li
      AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States
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    • John T. Randolph
      John T. Randolph
      AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States
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      Orcidhttps://orcid.org/0000-0001-6546-0276
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      Agnieszka K. Bischoff
      AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States
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      Julia Fitzgibbons
      AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States
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      Orcidhttps://orcid.org/0000-0003-3058-1048
    • Lu Wang
      Lu Wang
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      Lu Wang
      AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States
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    • Axel Hernandez Jr
      Axel Hernandez, Jr
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      Ying Jia
      AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States
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      Christian A. Goess
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      Shaughn H. Bryant
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    Other Access OptionsSupporting Information (3)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2024, 67, 11, 9495–9515
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    https://doi.org/10.1021/acs.jmedchem.4c00598
    Published May 23, 2024
    Copyright © 2024 American Chemical Society
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    Abstract

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    We describe the discovery of a thioester-containing glucocorticoid receptor modulator (GRM) payload and the corresponding antibody–drug conjugate (ADC). Payload 6 was designed for rapid hepatic inactivation to minimize systemic exposure of nonconjugated GRM. Mouse PK indicated that 6 is cleared 10-fold more rapidly than a first-generation GRM payload, resulting in 10-fold lower exposure and 3-fold decrease in Cmax. The anti-mTNF conjugate ADC5 fully inhibited inflammation in mouse contact hypersensitivity with minimal effects on corticosterone, a biomarker for systemic GRM effects, at doses up to and including 100 mg/kg. Concomitant inhibition of P1NP suggests potential delivery to cells involved in the remodeling of bone, which may be a consequence of TNF-targeting or bystander payload effects. Furthermore, ADC5 fully suppressed inflammation in collagen-induced arthritis mouse model after one 10 mg/kg dose for 21 days. The properties of the anti-hTNF conjugate were suitable for liquid formulation and may enable subcutaneous dosing.

    Copyright © 2024 American Chemical Society

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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.4c00598.

    • Dose response of prednisolone in mouse CHS; plasma stability of compound 6; plasma exposures for free-payloads in mouse CHS; mouse PK for ADC1 and ADC5; CHS data for nontargeting isotype ADC versus anti-mTNF; protocols for in vitro GRE luciferase reporter assay, K562 assays, and mineral corticoid receptor cell assays; protocols for binding assays for androgen, estrogen, and progesterone receptors; protocols for in vivo CHS and CIA mouse models; procedures for formulation assessment measurements: pI, viscosity, DSC, colloidal stability; tabulated NMR shift assignments for compounds 5, 6, and 9; 1H, 19F, COSY, HSQC, and HMBC NMR spectra for compounds 5, 6, 9; 1H, 13C, and 19F NMR spectra for compounds 3, 4, 7, 8, 10, and 11; 1H NMR spectra for drug-linkers DL2-DL7; HIC, SEC, and reduced mass data for ADC2-ADC8; and LCMS conditions (PDF)

    • Molecular formula strings and associated biochemical data for thioester GRM payloads (CSV)

    • Molecular formula strings and associated biochemical data for drug-linkers and ADCs (CSV)

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2024, 67, 11, 9495–9515
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.4c00598
    Published May 23, 2024
    Copyright © 2024 American Chemical Society
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