{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T18:23:00Z","timestamp":1793902980426,"version":"4.8.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T00:00:00Z","timestamp":1617235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Bruton tyrosine kinase (BTK) is expressed in B cells and innate immune cells, acting as an essential signaling element in multiple immune cell pathways. Selective BTK inhibition has the potential to target multiple immune-mediated disease pathways. Rilzabrutinib is an oral, reversible, covalent BTK inhibitor designed for immune-mediated diseases. We examined the pharmacodynamic profile of rilzabrutinib and its preclinical mechanisms of action. In addition to potent and selective BTK enzyme and cellular activity, rilzabrutinib inhibited activation and inflammatory activities of B cells and innate cells such as macrophages, basophils, mast cells, and neutrophils, without cell death (in human and rodent assay systems). Rilzabrutinib demonstrated dose-dependent improvement of clinical scores and joint pathology in a rat model of collagen-induced arthritis and demonstrated reductions in autoantibody-mediated Fc\u03b3R signaling in vitro and in vivo, with blockade of rat Arthus reaction, kidney protection in mouse Ab-induced nephritis, and reduction in platelet loss in mouse immune thrombocytopenia. Additionally, rilzabrutinib inhibited IgE-mediated, Fc\u03b5R-dependent immune mechanisms in human basophils and mast cell\u2013dependent mouse models. In canines with naturally occurring pemphigus, rilzabrutinib treatment resulted in rapid clinical improvement demonstrated by anti-inflammatory effects visible within 2 wk and all animals proceeding to complete or substantial disease control. Rilzabrutinib is characterized by reversible covalent BTK binding, long BTK residence time with low systemic exposure, and multiple mechanistic and biological effects on immune cells. Rilzabrutinib\u2019s unique characteristics and promising efficacy and safety profile support clinical development of rilzabrutinib for a broad array of immune-mediated diseases.<\/jats:p>","DOI":"10.4049\/jimmunol.2001130","type":"journal-article","created":{"date-parts":[[2021,3,5]],"date-time":"2021-03-05T19:42:47Z","timestamp":1614973367000},"page":"1454-1468","source":"Crossref","is-referenced-by-count":133,"title":["Preclinical Efficacy and Anti-Inflammatory Mechanisms of Action of the Bruton Tyrosine Kinase Inhibitor Rilzabrutinib for Immune-Mediated Disease"],"prefix":"10.1093","volume":"206","author":[{"given":"Claire L","family":"Langrish","sequence":"first","affiliation":[{"name":"Principia Biopharma Inc. , South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Michael","family":"Bradshaw","sequence":"additional","affiliation":[{"name":"Principia Biopharma Inc. , South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle R","family":"Francesco","sequence":"additional","affiliation":[{"name":"Principia Biopharma Inc. , South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7651-2203","authenticated-orcid":false,"given":"Timothy D","family":"Owens","sequence":"additional","affiliation":[{"name":"Principia Biopharma Inc. , South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7174-0482","authenticated-orcid":false,"given":"Yan","family":"Xing","sequence":"additional","affiliation":[{"name":"Principia Biopharma Inc. , South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Shu","sequence":"additional","affiliation":[{"name":"Principia Biopharma Inc. , South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"LaStant","sequence":"additional","affiliation":[{"name":"Principia Biopharma Inc. , South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelina","family":"Bisconte","sequence":"additional","affiliation":[{"name":"Principia Biopharma Inc. , South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8181-4484","authenticated-orcid":false,"given":"Catherine","family":"Outerbridge","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine, University of California Davis , Davis, CA 95616"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3103-6930","authenticated-orcid":false,"given":"Stephen D","family":"White","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine, University of California Davis , Davis, CA 95616"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald J","family":"Hill","sequence":"additional","affiliation":[{"name":"Principia Biopharma Inc. , South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8643-3218","authenticated-orcid":false,"given":"Ken A","family":"Brameld","sequence":"additional","affiliation":[{"name":"Principia Biopharma Inc. , South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M","family":"Goldstein","sequence":"additional","affiliation":[{"name":"Principia Biopharma Inc. , South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip A","family":"Nunn","sequence":"additional","affiliation":[{"name":"Principia Biopharma Inc. , South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,4,1]]},"reference":[{"key":"2025030417255542100_r1","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1111\/j.1600-065X.2008.00741.x","article-title":"Bruton\u2019s tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain","volume":"228","author":"Mohamed","year":"2009","journal-title":"Immunol. 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