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

Autor:	Marvin CC; AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Hobson AD; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States., McPherson MJ; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States., Hayes ME; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States., Patel MV; AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Schmidt DL; AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Li T; AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Randolph JT; AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Bischoff AK; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States., Fitzgibbons J; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States., Wang L; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States., Wang L; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States., Hernandez A Jr; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States., Jia Y; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States., Goess CA; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States., Bryant SH; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States., Mathieu SL; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States., Xu J; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Jun 13; Vol. 67 (11), pp. 9495-9515. Date of Electronic Publication: 2024 May 23.
DOI:	10.1021/acs.jmedchem.4c00598
Abstrakt:	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.
Databáze:	MEDLINE
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