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

J Med Chem. 2022 Dec 8;65(23):15893-15934. doi: 10.1021/acs.jmedchem.2c01579. Epub 2022 Nov 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Glucocorticoids*
  • Humans
  • Immunoconjugates* / pharmacology
  • Immunoconjugates* / therapeutic use
  • Mice
  • Receptors, Glucocorticoid
  • Tumor Necrosis Factor Inhibitors


  • Glucocorticoids
  • Immunoconjugates
  • Receptors, Glucocorticoid
  • Tumor Necrosis Factor Inhibitors
  • ABBV-3373