Design and Development of Glucocorticoid Receptor Modulators as Immunology Antibody-Drug Conjugate Payloads.

Autor:	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., Waegell W; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States., Goess CA; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States., Stoffel RH; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States., Li X; WuXi AppTec, 168 Nanhai Road, Tianjin Economic-Technological Development Area TEDA, Tianjin 300457, China., Zhou J; WuXi AppTec, 168 Nanhai Road, Tianjin Economic-Technological Development Area TEDA, Tianjin 300457, China., Wang Z; WuXi AppTec, 168 Nanhai Road, Tianjin Economic-Technological Development Area TEDA, Tianjin 300457, China., Yu Y; WuXi AppTec, 168 Nanhai Road, Tianjin Economic-Technological Development Area TEDA, Tianjin 300457, China., Hernandez A Jr; 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., 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., Pawlikowska M; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States., Puthenveetil S; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States., Santora LC; 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., Marvin CC; AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Hayes ME; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States., Shrestha A; AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Sarris KA; AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Li B; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2022 Mar 24; Vol. 65 (6), pp. 4500-4533. Date of Electronic Publication: 2022 Feb 08.
DOI:	10.1021/acs.jmedchem.1c02099
Abstrakt:	Glucocorticoid receptor modulators (GRM) are the first-line treatment for many immune diseases, but unwanted side effects restrict chronic dosing. However, targeted delivery of a GRM payload via an immunology antibody-drug conjugate (iADC) may deliver significant efficacy at doses that do not lead to unwanted side effects. We initiated our α-TNF-GRM ADC project focusing on identifying the optimal payload and a linker that afforded stable attachment to both the payload and antibody, resulting in the identification of the synthetically accessible maleimide-Gly-Ala-Ala linker. DAR 4 purified ADCs were shown to be more efficacious in a mouse contact hypersensitivity model than the parent α-TNF antibody. Analysis of P1NP and corticosterone biomarkers showed there was a sufficient therapeutic window between efficacy and unwanted effects. In a chronic mouse arthritis model, α-TNF-GRM ADCs were more efficacious than both the parent α-TNF mAb and an isotype control bearing the same GRM payload.
Databáze:	MEDLINE
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