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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.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2024 Jun 13; Vol. 67 (11), pp. 9495-9515. Date of Electronic Publication: 2024 May 23. - Publication Year :
- 2024
-
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.
- Subjects :
- Animals
Mice
Receptors, Glucocorticoid metabolism
Receptors, Glucocorticoid antagonists & inhibitors
Inflammation drug therapy
Inflammation metabolism
Glucocorticoids pharmacology
Humans
Male
Disease Models, Animal
Arthritis, Experimental drug therapy
Arthritis, Experimental metabolism
Immunoconjugates pharmacology
Immunoconjugates chemistry
Immunoconjugates pharmacokinetics
Immunoconjugates therapeutic use
Corticosterone blood
Tumor Necrosis Factor-alpha metabolism
Tumor Necrosis Factor-alpha antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 67
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38780432
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.4c00598