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.

本研究报道了一种含硫酯的糖皮质激素受体调节剂（glucocorticoid receptor modulator, GRM）药物有效载荷及其对应抗体偶联药物（antibody–drug conjugate, ADC）的研发情况。有效载荷6经设计可快速发生肝脏灭活，以最大限度降低未结合型GRM的全身暴露量。小鼠药代动力学实验结果显示，有效载荷6的清除速率较第一代GRM有效载荷快10倍，其全身暴露量降低10倍，峰浓度（Cmax）下降3倍。在最高至100 mg/kg的给药剂量下，抗鼠肿瘤坏死因子（anti-mTNF）偶联药物ADC5可完全抑制小鼠接触性超敏反应模型中的炎症反应，且对反映全身GRM效应的生物标志物皮质酮的影响极小。同时，该药物对I型前胶原N末端肽（P1NP）的抑制作用提示，其可能被递送至参与骨重塑的细胞中，这一效应可能源于肿瘤坏死因子靶向作用，或是有效载荷的旁观者效应。此外，单次给予10 mg/kg剂量的ADC5后，可在21天内完全抑制胶原诱导性关节炎小鼠模型的炎症反应。抗人肿瘤坏死因子（anti-hTNF）偶联药物的制剂特性适配液体制剂，有望实现皮下给药。