2. Academic Validation
  3. Development of Anti-CD74 Antibody-Drug Conjugates to Target Glucocorticoids to Immune Cells

Development of Anti-CD74 Antibody-Drug Conjugates to Target Glucocorticoids to Immune Cells

  • Bioconjug Chem. 2018 Jul 18;29(7):2357-2369. doi: 10.1021/acs.bioconjchem.8b00312.
Philip E Brandish 1,  Anthony Palmieri 1,  Svetlana Antonenko 1,  Maribel Beaumont 1,  Lia Benso 1,  Mark Cancilla 1,  Mangeng Cheng 1,  Laurence Fayadat-Dilman 1,  Guo Feng 1,  Isabel Figueroa 1,  Juhi Firdos 2,  Robert Garbaccio 1,  Laura Garvin-Queen 1,  Dennis Gately 2,  Prasanthi Geda 1,  Christopher Haines 1,  SuChun Hseih 1,  Douglas Hodges 1,  Jeffrey Kern 1,  Nickolas Knudsen 2,  Kristen Kwasnjuk 1,  Linda Liang 1,  Huiping Ma 1,  Anthony Manibusan 2,  Paul L Miller 1,  Lily Y Moy 1,  Yujie Qu 1,  Sanjiv Shah 1,  John S Shin 1,  Peter Stivers 1,  Ying Sun 2,  Daniela Tomazela 1,  Hyun Chong Woo 1,  Dennis Zaller 1,  Shuli Zhang 1,  Yiwei Zhang 1,  Mark Zielstorff 1
Affiliations

Affiliations

  • 1 Merck & Co., Inc. , 2000 Galloping Hill Road , Kenilworth , New Jersey 07033 , United States.
  • 2 Ambrx, Inc. , 10975 North Torrey Pines Road , La Jolla , California 92037 , United States.
PMID: 29923706 DOI: 10.1021/acs.bioconjchem.8b00312
Abstract

Glucocorticoids (GCs) are excellent anti-inflammatory drugs but are dose-limited by on-target toxicity. We sought to solve this problem by delivering GCs to immune cells with antibody-drug conjugates (ADCs) using antibodies containing site-specific incorporation of a non-natural amino acid, novel linker chemistry for in vitro and in vivo stability, and existing and novel Glucocorticoid Receptor (GR) agonists as payloads. We directed fluticasone propionate to human antigen-presenting immune cells to afford GR activation that was dependent on the targeted antigen. However, mechanism of action studies pointed to accumulation of free payload in the tissue culture supernatant as the dominant driver of activity and indeed administration of the ADC to human CD74 transgenic mice failed to activate GR target genes in splenic B cells. Suspecting dissipation of released payload, we designed an ADC bearing a novel GR agonist payload with reduced permeability which afforded cell-intrinsic activity in human B cells. Our work shows that antibody-targeting offers significant potential for rescuing existing and new dose-limited drugs outside the field of oncology.

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