An anti-TNF-glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases

Sci Transl Med. 2024 Mar 20;16(739):eadd8936. doi: 10.1126/scitranslmed.add8936. Epub 2024 Mar 20.

Abstract

Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti-tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti-TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti-TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti-TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti-TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment.

MeSH terms

  • Animals
  • Antibodies*
  • Arthritis, Experimental*
  • Disease Models, Animal
  • Glucocorticoids / pharmacology
  • Glucocorticoids / therapeutic use
  • Humans
  • Immunoconjugates* / pharmacology
  • Immunoconjugates* / therapeutic use
  • Mice
  • Pharmaceutical Preparations
  • Receptors, Glucocorticoid / therapeutic use
  • Steroids*
  • Tumor Necrosis Factor Inhibitors / therapeutic use
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • ABBV-3373
  • Pharmaceutical Preparations
  • Receptors, Glucocorticoid
  • Tumor Necrosis Factor Inhibitors
  • Glucocorticoids
  • Tumor Necrosis Factor-alpha
  • Immunoconjugates
  • Antibodies
  • Steroids