An anti–TNF–glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases
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Published:2024-03-20
Issue:739
Volume:16
Page:
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ISSN:1946-6234
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Container-title:Science Translational Medicine
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language:en
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Short-container-title:Sci. Transl. Med.
Author:
McPherson Michael J.1ORCID, Hobson Adrian D.1ORCID, Hernandez Axel1, Marvin Christopher C.2ORCID, Waegell Wendy1, Goess Christian1ORCID, Oh Jason Z.1ORCID, Shi Dan1ORCID, Hayes Martin E.1ORCID, Wang Lu1ORCID, Wang Lu1ORCID, Schmidt Diana2ORCID, Wang Zhi2ORCID, Pitney Victoria1, McCarthy Kimberley1ORCID, Jia Ying1ORCID, Wang Ce1ORCID, Kang Bit Na1ORCID, Bryant Shaughn1ORCID, Mathieu Suzanne1ORCID, Ruzek Melanie1ORCID, Parmentier Julie1, D’Cunha Ronilda R.2ORCID, Pang Yinuo2ORCID, Phillips Lucy1, Brown Nathan J.1ORCID, Xu Jianwen1ORCID, Graff Candace1ORCID, Tian Yu1ORCID, Longenecker Kenton L.2, Qiu Wei2ORCID, Zhu Haizhong2, Liu Wei3, Zheng Pingping3ORCID, Bi Yingtao1ORCID, Stoffel Robert1ORCID
Affiliation:
1. AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA. 2. AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064, USA. 3. AbbVie Bay Area, 1000 Gateway Boulevard, South San Francisco, CA 94080, USA.
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.
Publisher
American Association for the Advancement of Science (AAAS)
Cited by
3 articles.
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