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

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.