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

• DOI: 10.1126/scitranslmed.add8936
• Publication Date: 2024-03-20T17:58:36Z
• Authors: Michael J. McPherson; Adrian D. Hobson; Axel Hernandez; Christopher C. Ma...; Wendy Waegell; Christian Goess; Jason Z. Oh; Dan Shi; Martin E. Hayes; Lu Wang; Lu Wang; Diana Schmidt; Zhi Wang; Victoria Pitney; Kimberley McCarthy; Ying Jia; Ce Wang; Bit Na Kang; Shaughn Bryant; Suzanne Mathieu; Melanie Ruzek; Julie Parmentier; Ronilda R. D’Cunha; Yinuo Pang; Lucy Phillips; Nathan J. Brown; Jianwen Xu; Candace Graff; Yu Tian; Kenton L. Longene...; Wei Qiu; Haizhong Zhu; Wei Liu; Pingping Zheng; Yingtao Bi; Robert Stoffel
• Keywords: 0301 basic medicine; Immunoconjugates; Tumor Necrosis Factor-alpha; Arthritis, Experimental; Antibodies; Mice; Disease Models, Animal; 03 medical and health sciences; Receptors, Glucocorticoid; Pharmaceutical Preparations; Humans; Animals; Tumor Necrosis Factor Inhibitors; Steroids; Glucocorticoids

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