POS0365 ANTI-TNF GLUCOCORTICOID RECEPTOR MODULATOR ANTIBODY DRUG CONJUGATE FOR THE TREATMENT OF AUTOIMMUNE DISEASES

Abstract

Background:Glucocorticoids (GC) are potent drugs used for treating many inflammatory diseases. While GCs are effective in many immune diseases, dose and duration of administration is limited due to significant side effects. Resting immune cells have very little TNF expression on the cell surface and it is only in an activated state that TNF expression is upregulated. Upon immune cell stimulation, TNF is upregulated and although a significant amount of TNF is cleaved from an activated cell, a portion remains on the cell surface. We have observed that anti-TNF antibodies bind to transmembrane TNF (tmTNF) and undergo endocytosis to the lysosome (1). We have developed a stable antibody drug conjugate (ADC), ABBV-3373, that has a proprietary, highly potent, glucocorticoid receptor modulator (GRM) payload linked to an anti-TNF monoclonal antibody (mAb) that is able to deliver the GC payload to activated immune cells.Objectives:We hypothesized that a TNF ADC with a GRM payload would be able to deliver increased efficacy through both TNF inhibition and targeted GRM payload delivery to activated immune cells while sparing systemic glucocorticoid side effects.Methods:A mouse surrogate TNF GRM ADC was characterized in an acute in vivo contact hypersensitivity model of inflammation (CHS) and in a mouse model of collagen induced arthritis (mCIA). Additionally, the human anti-TNF GRM ADC, ABBV-3373 has been characterized in healthy volunteers.Results:In the CHS model the anti-TNF GRM ADC significantly inhibited the inflammatory response with minimal effect on systemic GC biomarkers. In mCIA a single dose of an anti-TNF GRM ADC, administered at disease onset, was able to completely inhibit arthritis for greater than 30 days while an anti-TNF mAb only partially inhibited disease. ABBV-3373, a human anti-TNF GRM ADC with a GC payload, was evaluated in a Phase 1 study in healthy volunteers. ABBV-3373 demonstrated antibody-like PK profile and ABBV-3373 did not impact cortisol levels at predicted efficacious doses while control subjects that received a single oral dose of 10 mg prednisone demonstrated expected decreases in cortisol levels.Conclusion:These data suggest that an anti-TNF ADC delivering a GRM payload into activated immune cells may provide improved efficacy in immune mediated diseases, while minimizing systemic side effects associated with standard GC treatment.