Design and Development of Glucocorticoid Receptor Modulators as Immunology Antibody-Drug Conjugate Payloads

J Med Chem. 2022 Mar 24;65(6):4500-4533. doi: 10.1021/acs.jmedchem.1c02099. Epub 2022 Feb 8.

Abstract

Glucocorticoid receptor modulators (GRM) are the first-line treatment for many immune diseases, but unwanted side effects restrict chronic dosing. However, targeted delivery of a GRM payload via an immunology antibody-drug conjugate (iADC) may deliver significant efficacy at doses that do not lead to unwanted side effects. We initiated our α-TNF-GRM ADC project focusing on identifying the optimal payload and a linker that afforded stable attachment to both the payload and antibody, resulting in the identification of the synthetically accessible maleimide-Gly-Ala-Ala linker. DAR 4 purified ADCs were shown to be more efficacious in a mouse contact hypersensitivity model than the parent α-TNF antibody. Analysis of P1NP and corticosterone biomarkers showed there was a sufficient therapeutic window between efficacy and unwanted effects. In a chronic mouse arthritis model, α-TNF-GRM ADCs were more efficacious than both the parent α-TNF mAb and an isotype control bearing the same GRM payload.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies
  • Antineoplastic Agents*
  • Immunoconjugates* / pharmacology
  • Immunoconjugates* / therapeutic use
  • Mice
  • Receptors, Glucocorticoid

Substances

  • Antibodies
  • Antineoplastic Agents
  • Immunoconjugates
  • Receptors, Glucocorticoid