Evaluating therapeutic plasma exchange and protease inhibitors as mechanisms to reduce soluble mesothelin

Our plain-English summary of Evaluating therapeutic plasma exchange and protease inhibitors as mechanisms to reduce soluble mesothelin, by K.E.R. Smith, J.R. Ayers-Ringler, J.J. Orme, et al (Scientific Reports, 2025).

The study

• Authors: K.E.R. Smith, J.R. Ayers-Ringler, J.J. Orme, F. Lucien, Y. Kim, J.L. Winters, A.S. Mansfield
• Journal: Scientific Reports
• Published: 2025;15(1):13174
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Cell surface mesothelin (MSLN) can be solubilized and released into the systemic circulation. 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 (p < 0.05) and reduced cytotoxicity of anetumab ravtansine in the presence of recombinant MSLN in cell lines, a surrogate for sMSLN. TPE consistently reduced sMSLN (p < 0.05) with an average decrease of 43.6% (15.4 ng/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.

© 2025. The Author(s).

In plain English

This laboratory study asked whether soluble mesothelin, a protein shed from the surface of cells including mesothelioma cells, interferes with anetumab, an antibody against mesothelin, and with anetumab ravtansine, a drug that links that antibody to a toxin. It also tested ways to lower soluble mesothelin. The study did not examine asbestos exposure. The authors measured soluble mesothelin in stored blood plasma from 15 patients who had a routine therapeutic plasma exchange, a procedure that removes and replaces blood plasma, for conditions other than mesothelioma. After one exchange, levels fell in all 15 patients, by an average of 43.6% or 15.4 ng/mL (p = 0.031). In two plasma samples, anetumab attached to beads lowered measured mesothelin. In a mesothelioma cell line, added mesothelin protein was linked to less drug effect on cell coverage at one dose. Two protease-blocking drugs, marimastat and TMI-1, gave hard-to-interpret results, and the two combined harmed cells on their own. The authors concluded that plasma exchange could offer a way to reduce soluble mesothelin. They said larger studies are needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: measurement of soluble mesothelin in stored paired plasma samples taken before and after therapeutic plasma exchange, immunoprecipitation experiments, and cell-line cytotoxicity experiments
• Who was studied: 15 patients undergoing routine therapeutic plasma exchange for various medical conditions, none listed as mesothelioma, enrolled at Mayo Clinic between December 2019 and March 2020 as part of an earlier study. Cell experiments used the epithelioid mesothelioma cell line Mero-95.
• Exposure: No asbestos exposure was studied. The interventions examined were one plasma volume of therapeutic plasma exchange with albumin replacement; anetumab-conjugated beads at 12.5, 25 and 37.5 µg/mL; anetumab ravtansine at 10, 50 and 100 nM; recombinant mesothelin at 3 nM; and the protease inhibitors marimastat and TMI-1, each at 10 µM, alone or combined.
• Main results:
  • In the 15 patients, one plasma exchange reduced soluble mesothelin by an average of 43.6% or 15.4 ng/mL (p = 0.031).
  • Soluble mesothelin fell in every one of the 15 patients. Per-patient decreases in Table 2 ranged from 18.31% to 93.36%.
  • In two randomly selected plasma samples, anetumab-conjugated beads significantly reduced measured soluble mesothelin (p < 0.05).
  • The size of the reduction differed between the two samples. In the first sample it was 45.6% to 64.5%. In the second, starting at 7.231 ng/mL, it was only 7.3% to 13.7%.
  • In Mero-95 cells before any anetumab ravtansine was added, marimastat and TMI-1 combined lowered cell viability, compared with no pretreatment (mean difference 48.25%, p = 0.0042) and with DMSO control (mean difference 53%, p = 0.0016). The authors suggested this reflects a direct cytotoxic effect of the combination.
  • At 10 nM anetumab ravtansine, the figure legend reports higher confluence (less cytotoxicity) with recombinant mesothelin than with: DMSO control (p = 0.0348), TMI-1 (p = 0.0289), and the combination (p = 0.0206). It reports no significant difference compared with marimastat alone (p = 0.0679).
  • At 100 nM anetumab ravtansine, the groups showed no significant differences in viability or confluence, apart from reduced viability with the combined protease inhibitors.
• The authors' conclusion: The authors concluded that high soluble mesothelin represents a mechanism of resistance to anti-mesothelin antibody-based therapies. They also concluded that TMI-1 may stabilize mesothelin at the cell surface and that therapeutic plasma exchange could offer a novel approach to reduce soluble mesothelin.
• Limitations the authors state:
  • Only 15 patients were studied, fewer than the 24 in a comparable earlier study of soluble PD-L1.
  • The plasma samples came from frozen storage from an earlier study, and results are available after only one plasma exchange session.
  • The reduction in soluble mesothelin varied widely between patients.
  • The protease inhibitor results are hard to interpret because the combination may itself be toxic to cells.
  • The 100 nM experiments had low cell counts.
  • The findings need prospective validation in a larger group of patients.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelin, Biomarker.

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