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J Med Chem ; 67(11): 9495-9515, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38780432

RESUMEN

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.


Asunto(s)
Artritis Experimental , Corticosterona , Inmunoconjugados , Factor de Necrosis Tumoral alfa , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Ratones , Inmunoconjugados/farmacología , Inmunoconjugados/química , Inmunoconjugados/farmacocinética , Inmunoconjugados/uso terapéutico , Corticosterona/sangre , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/antagonistas & inhibidores , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Glucocorticoides/farmacología , Humanos , Masculino , Modelos Animales de Enfermedad
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