{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:13:40Z","timestamp":1790741620386,"version":"4.1.0"},"reference-count":31,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Rheumatoid arthritis (RA) is an autoimmune disorder characterized by synovial inflammation and progressive joint destruction. There is no cure, and patient responses to current therapies vary, reflecting underlying pathogenic heterogeneity. Leveraging single-cell RNA sequencing (scRNA-seq) of RA synovium, we identified a PLAUR\/uPAR-high myeloid subset that co-expresses pathogenic mediators, including IL1B and CXCL8. To target these cells, we developed anti-uPAR antibody\u2013drug conjugates (ADCs) and evaluated various payloads in vitro and in vivo. ADCs bearing BCL-2 family inhibitors selectively induced apoptosis in proinflammatory human monocytes and macrophages with elevated uPAR, while sparing unstimulated monocytes with low basal uPAR in vitro. The treatment also reduced CXCL8 secretion. Given that murine myeloid cells exhibited lower uPAR expression and reduced sensitivity to BCL-2 family inhibitors, we used a monomethyl auristatin F (MMAF) payload to demonstrate in vivo proof-of-concept. In an air-pouch model, the anti-uPAR\u2013MMAF conjugate reduced uPARhighCD11b+F4\/80+ macrophages by 39% compared with the isotype control. Together, our study underscores the potential of ADCs to eliminate disease-relevant cell types with inducible cell surface markers. This work opens new avenues for exploring cytotoxic ADCs as targeted therapies for autoimmune and inflammatory diseases.<\/jats:p>","DOI":"10.3390\/cells15090803","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T13:32:22Z","timestamp":1777469542000},"page":"803","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["uPAR-Targeting Cytotoxic Antibody\u2013Drug Conjugates Selectively Deplete Proinflammatory Myeloid Cells for Autoimmune Indications"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7957-7336","authenticated-orcid":false,"given":"Handan","family":"Xiang","sequence":"first","affiliation":[{"name":"Discovery Immunology, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace Pham","family":"Mortenson","sequence":"additional","affiliation":[{"name":"Discovery Biologics, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon B.","family":"Lang","sequence":"additional","affiliation":[{"name":"Discovery Chemistry, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sriram","family":"Jakkaraju","sequence":"additional","affiliation":[{"name":"Discovery Biologics, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anirudh","family":"Chirala","sequence":"additional","affiliation":[{"name":"Discovery Immunology, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimin","family":"Zhu","sequence":"additional","affiliation":[{"name":"Quantitative Biosciences, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengxuan","family":"Jia","sequence":"additional","affiliation":[{"name":"Pharmacokinetics, Dynamics, Metabolism and Bioanalytics, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianzhong","family":"Wen","sequence":"additional","affiliation":[{"name":"Pharmacokinetics, Dynamics, Metabolism and Bioanalytics, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Chen","sequence":"additional","affiliation":[{"name":"Pharmacokinetics, Dynamics, Metabolism and Bioanalytics, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0196-8828","authenticated-orcid":false,"given":"Arjun","family":"Baghela","sequence":"additional","affiliation":[{"name":"Data, AI and Genome Sciences, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen-Cheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Chemical Biology, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3532-9653","authenticated-orcid":false,"given":"Marc A.","family":"Sze","sequence":"additional","affiliation":[{"name":"Data, AI and Genome Sciences, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laxminarayan G.","family":"Hegde","sequence":"additional","affiliation":[{"name":"Quantitative Biosciences, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhang-Hoover","sequence":"additional","affiliation":[{"name":"Quantitative Biosciences, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aarron","family":"Willingham","sequence":"additional","affiliation":[{"name":"Discovery Biologics, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahisa","family":"Handa","sequence":"additional","affiliation":[{"name":"Discovery Biologics, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An","family":"Chi","sequence":"additional","affiliation":[{"name":"Chemical Biology, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2762-6906","authenticated-orcid":false,"given":"Gretchen A.","family":"Baltus","sequence":"additional","affiliation":[{"name":"Discovery Immunology, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajesh V.","family":"Kamath","sequence":"additional","affiliation":[{"name":"Discovery Immunology, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc C.","family":"Levesque","sequence":"additional","affiliation":[{"name":"Discovery Immunology, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8569-515X","authenticated-orcid":false,"given":"Elisabeth H.","family":"Vollmann","sequence":"additional","affiliation":[{"name":"Discovery Immunology, Merck & Co., Inc., Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1007\/s00296-020-04731-0","article-title":"The global prevalence of rheumatoid arthritis: A meta-analysis based on a systematic review","volume":"41","author":"Almutairi","year":"2020","journal-title":"Rheumatol. 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