2. Academic Validation
  3. Discovery of ABBV-3373, an Anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody Drug Conjugate

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

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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