2. Academic Validation
  3. Anti-TNF Thioester Glucocorticoid Antibody-Drug Conjugate Fully Inhibits Inflammation with Minimal Effect on Systemic Corticosterone Levels in a Mouse Arthritis Model

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

  • J Med Chem. 2024 Jun 13;67(11):9495-9515. doi: 10.1021/acs.jmedchem.4c00598.
Christopher C Marvin 1,  Adrian D Hobson 2,  Michael J McPherson 2,  Martin E Hayes 2,  Meena V Patel 1,  Diana L Schmidt 1,  Tongmei Li 1,  John T Randolph 1,  Agnieszka K Bischoff 2,  Julia Fitzgibbons 2,  Lu Wang 2,  Lu Wang 2,  Axel Hernandez Jr 2,  Ying Jia 2,  Christian A Goess 2,  Shaughn H Bryant 2,  Suzanne L Mathieu 2,  Jianwen Xu 2
Affiliations

Affiliations

  • 1 AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
  • 2 AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States.
PMID: 38780432 DOI: 10.1021/acs.jmedchem.4c00598
Abstract

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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