Novel Antibody Therapeutics Targeting Mesothelin In Solid Tumors

Our plain-English summary of Novel Antibody Therapeutics Targeting Mesothelin In Solid Tumors, by X.Y. Zhao, B. Subramanyam, N. Sarapa, et al (Clinical Cancer Drugs, 2016).

The study

• Authors: X.Y. Zhao, B. Subramanyam, N. Sarapa, S. Golfier, H. Dinter
• Journal: Clinical Cancer Drugs
• Published: 2016;3(2):76-86
• Cited by: 42 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Abstract Background: Monoclonal antibodies have become attractive clinical anti-cancer drugs in the last 3 decades due to their targeting specificity and suitable pharmacokinetic properties. Mesothelin is a tumor-associated antigen with limited expression in normal tissues. It is frequently over-expressed on the cell membrane of a number of epithelial malignancies (e.g. mesothelioma, pancreatic, ovarian, lung, triple negative breast and gastric cancers).

Methods: Mesothelin is validated as a suitable antibody target for cancer therapy. A number of novel antibody therapeutics targeting mesothelin in development are compared and their mechanisms of action are also discussed. Both basic science and clinical data are provided to give a complete veiw of how an agent is developed from bench to bedside.

Results: Novel antibody therapeutics, including unconjugated monoclonal antibodies, recombinant immunotoxins and antibody-drug conjugates, targeting mesothelin exert anti-tumor activities by different mechanisms of action. Based on the convincing preclinical data generated with these molecules, the antibody therapeutics have been brought into early clinical evaluation where initial promising results were obtained.

Conclusion: These antibody therapeutics directed against mesothelin are expected to have different safety profiles, based on their different mechanism of action. Further clinical development will reveal which of these molecules shows the best efficacy and widest therapeutic window and thus is best suited to bring benefit to the patients.

In plain English

This article was a review, not a study of asbestos exposure. The authors described experimental antibody-based cancer drugs aimed at mesothelin, a protein found on mesothelioma cells and on several other cancers, including pancreatic and ovarian cancer. They covered unconjugated antibodies (amatuximab), toxin-linked antibodies (SS1P and RG7787) and antibody-drug conjugates (anetumab ravtansine, DMOT4039A and others), mostly by summarizing other researchers' laboratory, animal and early clinical studies. In one trial they described, 89 patients with unresectable malignant pleural mesothelioma received amatuximab with chemotherapy. The article reported partial tumor responses in 33 patients (40%) but did not say how many patients that percentage was based on. The authors also reported their own laboratory test in one cell line, NCI-H226, which they described as a human lung squamous carcinoma and mesothelioma cell line. The test showed that mesothelin was taken inside these cells after an antibody bound to it. The authors concluded that these drugs work in different ways, are expected to have different safety profiles, and that further clinical development will reveal which one works best. All authors stated that they were employees of Bayer, which makes one of the drugs reviewed.

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: Review article of antibody-based drugs targeting mesothelin, including some of the authors' own laboratory data
• Who was studied: Drugs in development and the published preclinical and clinical studies of them (cell lines, mouse and monkey studies, and early-phase trials in patients with mesothelioma, pancreatic, ovarian and other cancers)
• Exposure: No asbestos exposure was studied. The agents reviewed were mesothelin-targeting unconjugated monoclonal antibodies, recombinant immunotoxins and antibody-drug conjugates.
• Main results:
  • In the authors' own live-cell test in one cell line, NCI-H226 (described as a human lung squamous carcinoma and mesothelioma cell line), mesothelin was taken into the cells after antibody binding at 37 degrees C but not at 4 degrees C.
  • In a cited Phase II trial of amatuximab with pemetrexed and cisplatin, 89 patients with unresectable malignant pleural mesothelioma received combination treatment. The article reported 33 (40%) patients with partial response and 42 (51%) with stable disease, without stating the number of patients these percentages were based on.
  • In a cited Phase I trial of SS1P given alone by bolus injection, neutralizing antibodies against the toxin part (PE38) developed in 88% of patients in the first treatment cycle.
  • In a cited ongoing Phase 1 study of SS1P with cisplatin and pemetrexed in chemotherapy-naive patients with advanced pleural mesothelioma, 10 (77%) of 13 evaluable patients had a partial response at the maximum tolerated dose.
  • In a cited Phase 1 study of anetumab ravtansine in 77 cancer patients, the maximum tolerated dose was 6.5 mg/kg. At that dose the article reported a partial response in 6 patients (19%) and stable disease in 18 patients (47%), as printed, without stating the denominator. Keratitis and neuropathy were among the side effects that led to dose reductions.
  • In a cited Phase I study of DMOT4039A in 49 patients with pancreatic or ovarian cancer, 4 patients (8%) had a confirmed partial response. The maximum tolerated dose was 2.4 mg/kg.
• The authors' conclusion: The authors concluded that these mesothelin-targeting antibody drugs work by different mechanisms and are expected to have different safety profiles. They stated that early clinical results were promising and that further clinical development will reveal which molecule has the best efficacy and widest therapeutic window.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelin, Monoclonal Antibody, Mesothelioma, Stomach Cancer.

Related studies

• Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect — S. Golfier, C. Kopitz, et al. (2014)
• First-in-human study of a thorium-227-labeled mesothelin-targeting antibody-chelator conjugate (MSLN-TTC), in patients with malignant mesothelioma and other solid tumors — A. Minchom, O. Lindén, et al. (2025)
• Phase I study of amatuximab, a novel monoclonal antibody to mesothelin, in Japanese patients with advanced solid tumors — Y. Fujisaka, T. Kurata, et al. (2015)
• Amatuximab and novel agents targeting mesothelin for solid tumors — P. Baldo, S. Cecco (2017)
• Mesothelin-targeting T cells bearing a novel T cell receptor fusion construct (TRuC) exhibit potent antitumor efficacy against solid tumors — J. Ding, S. Guyette, et al. (2023)
• First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody-Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors — R. Hassan, G.R. Blumenschein, et al. (2020)

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