Glucocorticoids (GCs) are highly effective in the treatment of inflammatory and autoimmune diseases, due to their profound immune-modulatory actions. However, their use is limited by adverse effects associated with high doses and long-term use, including osteoporosis, weight gain, hyperglycemia, and hypertension.
To improve the safety profile of GCs through selective delivery to activated immune cells, McPherson et al. develop an antibody drug conjugate (ADC)-based approach. The ADC is comprised of the anti-tumour necrosis factor (TNF) antibody adalimumab (previously shown to bind to transmembrane TNF on activated immune cells and undergo internalization) conjugated to a GC receptor modulator (GRM; to dampen immune activity).
In vitro, uptake of this anti–TNF-GRM ADC (ABBV-3373) into activated human immune cells led to GRM release and inhibition of cytokine secretion. A surrogate mouse anti–TNF-GRM ADC reduced inflammatory responses in a mouse model of contact hypersensitivity when given prophylactically and reduced pathology of collagen-induced arthritis when given either at disease onset or at the peak of disease. The ADC displayed enhanced efficacy compared with the anti-TNF antibody and systemic effects were minimal. ABBV-3373 exhibited favourable pharmacokinetics and safety in a phase 1 study in healthy volunteers and is now in a clinical trial in patients with rheumatoid arthritis.
