Discovery of ABBV-3373, an Anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody Drug Conjugate

Using
a convergent synthetic route to enable multiple points of
diversity, a series of glucocorticoid receptor modulators (GRM) were
profiled for potency, selectivity, and drug-like properties in vitro. Despite covering a large range of diversity, profiling
the nonconjugated small molecule was suboptimal and they were conjugated
to a mouse antitumor necrosis factor (TNF) antibody using the MP-Ala-Ala
linker. Screening of the resulting antibody drug conjugates (ADCs)
provided a better assessment of efficacy and physical properties,
reinforcing the need to conduct structure–activity relationship
studies on the complete ADC. DAR4 ADCs were screened in an acute mouse
contact hypersensitivity model measuring biomarkers to ensure a sufficient
therapeutic window. In a chronic mouse arthritis model, mouse anti-TNF
GRM ADCs were efficacious after a single dose of 10 mg/kg i.p. for
over 30 days. Data on the unconjugated payloads and mouse surrogate
anti-TNF ADCs identified payload 17 which was conjugated
to a human anti-TNF antibody and advanced to the clinic as ABBV-3373.