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.
Adrian D Hobson  1 ,  Michael J McPherson  1 ,  Martin E Hayes  1 ,  Christian Goess  1 ,  Xiang Li  2 ,  Jian Zhou  2 ,  Zhongyuan Wang  2 ,  Yajie Yu  2 ,  Jindong Yang  2 ,  Liang Sun  2 ,  Qiang Zhang  2 ,  Pei Qu  2 ,  Shi Yang  2 ,  Axel Hernandez Jr  1 ,  Shaughn H Bryant  1 ,  Suzanne L Mathieu  1 ,  Agnieszka K Bischoff  1 ,  Julia Fitzgibbons  1 ,  Ling C Santora  1 ,  Lu Wang  1 ,  Lu Wang  1 ,  Margaret M Fettis  1 ,  Xiaofeng Li  2 ,  Christopher C Marvin  3 ,  Zhi Wang  3 ,  Meena V Patel  3 ,  Diana L Schmidt  3 ,  Tongmei Li  3 ,  John T Randolph  3 ,  Rodger F Henry  3 ,  Candace Graff  1 ,  Yu Tian  1 ,  Ana L Aguirre  3 ,  Anurupa Shrestha  3
Affiliations
  • 1. AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States.
  • 2. WuXi AppTec, 168 Nanhai Road, Tianjin Economic-Technological Development Area TEDA, Tianjin 300457, China.
  • 3. AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
PMID: 36394224 DOI: 10.1021/acs.jmedchem.2c01579
Abstract

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.

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