2. Academic Validation
  3. Discovery of ABBV-154, an anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody-Drug Conjugate (iADC)

Discovery of ABBV-154, an anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody-Drug Conjugate (iADC)

  • J Med Chem. 2023 Sep 14;66(17):12544-12558. doi: 10.1021/acs.jmedchem.3c01174.
Adrian D Hobson 1,  Jianwen Xu 1,  Dennie S Welch 2,  Christopher C Marvin 3,  Michael J McPherson 1,  Bradley Gates 2,  Xiaoli Liao 2,  Markus Hollmann 4,  Michael J Gattner 4,  Kristina Dzeyk 4,  Hetal Sarvaiya 5,  Vikram M Shenoy 5,  Margaret M Fettis 1,  Agnieszka K Bischoff 1,  Lu Wang 1,  Ling C Santora 1,  Lu Wang 1,  Julia Fitzgibbons 1,  Paulin Salomon 1,  Axel Hernandez Jr 1,  Ying Jia 1,  Christian A Goess 1,  Suzanne L Mathieu 1,  Shaughn H Bryant 1,  Mary E Larsen 1,  Baoliang Cui 1,  Yu Tian 1
Affiliations

Affiliations

  • 1 AbbVie Bioresearch Center, 381 Plantation Street, Worcester, Massachusetts 01605, United States.
  • 2 AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
  • 3 AbbVie Inc., 1400 Sheridan Road, North Chicago, Illinois 60064, United States.
  • 4 AbbVie Deutschland GmbH & Co KG, Knollstrasse 50, 67061 Ludwigshafen, Germany.
  • 5 AbbVie Inc., 1000 Gateway Blvd, South San Francisco, California 94080, United States.
PMID: 37656698 DOI: 10.1021/acs.jmedchem.3c01174
Abstract

Stable attachment of drug-linkers to the antibody is a critical requirement, and for maleimide conjugation to cysteine, it is achieved by ring hydrolysis of the succinimide ring. During ADC profiling in our in-house property screening funnel, we discovered that the succinimide ring open form is in equilibrium with the ring closed succinimide. Bromoacetamide (BrAc) was identified as the optimal replacement, as it affords stable attachment of the drug-linker to the antibody while completely removing the undesired ring open-closed equilibrium. Additionally, BrAc also offers multiple benefits over maleimide, especially with respect to homogeneity of the ADC structure. In combination with a short, hydrophilic linker and phosphate prodrug on the payload, this afforded a stable ADC (ABBV-154) with the desired properties to enable long-term stability to facilitate subcutaneous self-administration.

Figures
Products