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J Med Chem ; 65(6): 4500-4533, 2022 03 24.
Artículo en Inglés | MEDLINE | ID: mdl-35133822

RESUMEN

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.


Asunto(s)
Antineoplásicos , Inmunoconjugados , Animales , Anticuerpos , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Ratones , Receptores de Glucocorticoides
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