Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti–tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti–TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti–TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti–TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti–TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment.

中文翻译：

---

抗TNF-糖皮质激素受体调节剂抗体-药物偶联物可有效对抗免疫介导的炎症性疾病

糖皮质激素（GC）是治疗多种炎症性疾病的有效药物，但由于严重的副作用，给药剂量和持续时间受到限制。因此，我们试图找到一种方法来选择性地将 GC 靶向发炎组织。先前的研究发现，与跨膜 TNF 结合的抗肿瘤坏死因子 (TNF) 抗体会发生内化；因此，抗 TNF 抗体药物偶联物 (ADC) 在机制上是相似的，其中溶酶体分解代谢可以释放 GC 受体调节剂 (GRM) 有效负载以抑制免疫细胞活性。因此，我们生成了一种抗 TNF-GRM ADC，旨在抑制受刺激的人类免疫细胞产生促炎细胞因子。在接触性超敏反应的急性小鼠模型中，小鼠替代抗 TNF-GRM ADC 抑制炎症反应，对全身 GC 生物标志物影响最小。此外，在胶原诱发关节炎的小鼠模型中，在疾病发作时单剂量施用 ADC 能够完全抑制关节炎超过 30 天，而抗 TNF 单克隆抗体只能部分抑制疾病。在疾病高峰期进行 ADC 治疗也能够减轻关节炎表型。来自健康志愿者单次递增剂量 1 期研究的人抗 TNF-GRM ADC (ABBV-3373) 的临床数据证明了抗体样药代动力学特征，并且在预测治疗剂量下对血清皮质醇浓度缺乏影响。这些数据表明，在免疫介导的疾病中，抗 TNF-GRM ADC 可以提供比单独抗 TNF 更高的疗效，同时最大限度地减少与标准 GC 治疗相关的全身副作用。