Anti-TNF Thioester Glucocorticoid Antibody–Drug Conjugate Fully Inhibits Inflammation with Minimal Effect on Systemic Corticosterone Levels in a Mouse Arthritis ModelClick to copy article linkArticle link copied!
- Christopher C. Marvin*Christopher C. Marvin*Email: [email protected]AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United StatesMore by Christopher C. Marvin
- Adrian D. HobsonAdrian D. HobsonAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Adrian D. Hobson
- Michael J. McPhersonMichael J. McPhersonAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Michael J. McPherson
- Martin E. HayesMartin E. HayesAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Martin E. Hayes
- Meena V. PatelMeena V. PatelAbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United StatesMore by Meena V. Patel
- Diana L. SchmidtDiana L. SchmidtAbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United StatesMore by Diana L. Schmidt
- Tongmei LiTongmei LiAbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United StatesMore by Tongmei Li
- John T. RandolphJohn T. RandolphAbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United StatesMore by John T. Randolph
- Agnieszka K. BischoffAgnieszka K. BischoffAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Agnieszka K. Bischoff
- Julia FitzgibbonsJulia FitzgibbonsAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Julia Fitzgibbons
- Lu WangLu WangAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Lu Wang
- Lu WangLu WangAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Lu Wang
- Axel Hernandez JrAxel Hernandez, JrAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Axel Hernandez, Jr
- Ying JiaYing JiaAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Ying Jia
- Christian A. GoessChristian A. GoessAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Christian A. Goess
- Shaughn H. BryantShaughn H. BryantAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Shaughn H. Bryant
- Suzanne L. MathieuSuzanne L. MathieuAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Suzanne L. Mathieu
- Jianwen XuJianwen XuAbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United StatesMore by Jianwen Xu
Abstract
![Abstract Image](/cms/10.1021/acs.jmedchem.4c00598/asset/images/medium/jm4c00598_0010.gif)
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.
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