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The resulting soluble MSLN (sMSLN) may interfere with therapies targeting surface MSLN. We investigated the effects of sMSLN on anetumab, an antibody-based therapy against MSLN, anetumab ravtansine, an antibody drug conjugate, and mechanisms to decrease sMSLN. Whole blood samples were collected before and after one plasma volume of therapeutic plasma exchange (TPE). sMSLN levels were measured with ELISA assays in matched pre- and post-TPE plasma samples, and anetumab-immunoprecipitated samples. We also used protease inhibitors (PIs) as a mechanism to stabilize surface MSLN, then evaluated the cytotoxic effects of anetumab ravtansine. Our findings indicate that sMSLN sequesters and may impair the efficacy of this anti-MSLN antibody based on results showing that anetumab decreases the concentration of MSLN in plasma (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) and reduced cytotoxicity of anetumab ravtansine in the presence of recombinant MSLN in cell lines, a surrogate for sMSLN. TPE consistently reduced sMSLN (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) with an average decrease of 43.6% (15.4\u00a0ng\/mL). Surface MSLN stabilization was inconsistently observed with PIs. Overall, sMSLN could represent a predictive biomarker for MSLN directed therapies. TPE may be more reliable than PIs to reduce sMSLN and ultimately restore sensitivity to these therapies in patients with high sMSLN.<\/jats:p>","DOI":"10.1038\/s41598-025-97952-x","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T15:15:51Z","timestamp":1744816551000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Evaluating therapeutic plasma exchange and protease inhibitors as mechanisms to reduce soluble mesothelin"],"prefix":"10.1038","volume":"15","author":[{"given":"Katherine E. 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FL reports receiving research support to institution from Nanotics LLC; serving as scientific consultant for Mursla Bio; receiving royalties from Early is Good. AM reports receiving support from Genentech and Janssen for manuscript publication; receiving research support to institution from Novartis and Verily; receiving honoraria to institution for participation on advisory boards for AbbVie, AstraZeneca, Bristol-Myers Squibb, Genentech, Janssen and Takeda Oncology; serving as steering committee member for Janssen and Johnson & Johnson Global Services; having speaking engagements from Chugai Pharmaceutical Co., Ltd. (Roche); serving as grant reviewer for Rising Tide; having expert think tank participation in TRIPTYCH Health Partners; serving as a moderator for Ideology Health LLC (formerly Nexus Health Media); having CME presentation for Intellisphere LLC (OncLive Summit Series) and Answers in CME; having presentation for Immunocore; serving on the advisory board for Sanofi Genzyme; receiving honoraria to self for CME presentation for Antoni van Leeuwenhoek Kanker Instituut and MJH Life Sciences (OncLive); having presented to the University of Miami International Mesothelioma Symposium; receiving travel support from Roche; serving as nonremunerated director of the Mesothelioma Applied Research Foundation and member of the Friends of Patan Hospital Board of Directors; and receiving study funding and article process charges from Bristol-Myers Squibb. He has been supported by a Mark Foundation ASPIRE Award, Thymic Carcinoma Center Research Award, Department of Defense Concept Award W81XWH-22-1-0021, NCI R21 (CA251923), NCI R33 (CA272271), and NCI U24 (CA283479).  The remaining authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The TPE portion of this manuscript was part of a study approved by the Mayo Clinic Institutional Review Board (IRB# 19-008055). All patients (or legal guardians) provided informed consent to participate in this study and all experiments were performed within our institutional guidelines and regulations and in accordance with the Declaration of Helsinki.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"13174"}}