Medical application of the monoclonal antibody SKM9-2 against sialylated HEG1, a new precision marker for malignant mesothelioma

Our plain-English summary of Medical application of the monoclonal antibody SKM9-2 against sialylated HEG1, a new precision marker for malignant mesothelioma, by S. Tsuji, K. Imai (Proceedings of the Japan Academy. Series B, Physical and Biological Sciences, 2023).

The study

• Authors: S. Tsuji, K. Imai
• Journal: Proceedings of the Japan Academy. Series B, Physical and Biological Sciences
• Published: 2023;99(2):39-47
• Type of article: Review
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive tumor of the pleural cavity. Pathologically distinguishing MPM from other pleural lesions is often difficult. We searched for marker antigens to facilitate the pathological diagnosis of MPM and found useful markers for the pathological detection of malignant mesothelioma. Among them, the anti-mesothelioma monoclonal antibody SKM9-2, which was isolated as a clone binding to specimens of MPM (but not to specimens of lung adenocarcinoma) by immunohistochemical screening, showed higher specificity and sensitivity than traditional mesothelioma markers. SKM9-2 recognizes both sialylated O-glycans and peptide sequences in HEG1, and its glycan modifications are specific to mesothelioma. New effective treatments for MPM are needed because the prognosis of patients with MPM is usually poor. SKM9-2 can be used as a seed for next-generation antibody drugs with strong cytotoxic activities. In this review, we have summarized our research on antibody development for MPM diagnosis and treatment.

In plain English

This review summarized the authors' research, and related studies by other groups, on antibodies for diagnosing and treating malignant pleural mesothelioma (MPM). It did not study asbestos exposure, mentioning asbestos only as the disease's cause. They also described intelectin-1, found in 88.5% of epithelioid-type MPM. They focused mainly on SKM9-2, an antibody recognizing a sugar-modified (sialylated) form of the protein HEG1. In the authors' first study, SKM9-2 detected 98% (89/91) of epithelioid, 90% (19/21) of biphasic and 64% (9/14) of sarcomatoid MPM cases. Pooling three studies, one including mesotheliomas outside the pleura, the authors reported that SKM9-2 detected 97% (276/286) of epithelioid, 93% (83/89) of biphasic and 62% (45/73) of sarcomatoid mesotheliomas. For calretinin, the figures were 92% (232/253), 70% (48/69) and 19% (8/42). In pleural fluid, one cited study found SKM9-2 staining in 41 of 41 mesothelioma cases. It also found strong staining of reactive, non-cancerous mesothelial cells in 20 of 26 cases. The authors concluded that SKM9-2 is a sensitive marker for various mesothelioma types, and proposed it as a basis for antibody drugs. They noted that its safety in healthy organs is hard to confirm.

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 of the authors' own research and related published studies on mesothelioma marker antibodies
• Who was studied: Tissue and pleural effusion specimens from mesothelioma and non-mesothelial tumors, as reported in the authors' studies and in studies by Naso et al. and Hiroshima et al. The Hiroshima et al. tissue study also included peritoneal mesotheliomas, a mesothelioma of the tunica vaginalis and one well-differentiated papillary mesothelioma.
• Exposure: No asbestos exposure was studied. The article studied the antibody marker SKM9-2 (sialylated HEG1) and intelectin-1. Asbestos was mentioned only as background, as the cause of MPM.
• Main results:
  • In the authors' first study, SKM9-2 antigen was positive in 98% (89/91) of epithelioid-type MPM, 90% (19/21) of biphasic MPM and 64% (9/14) of sarcomatoid-type MPM
  • Pooled across three studies of malignant mesothelioma, positivity rates for the epithelioid, biphasic and sarcomatoid types were as follows. SKM9-2: 97% (276/286), 93% (83/89) and 62% (45/73). Calretinin: 92% (232/253), 70% (48/69) and 19% (8/42). WT-1: 81%, 48% and 24%. Podoplanin: 84%, 52% and 45%.
  • One of the pooled studies (Hiroshima et al.) included mesotheliomas outside the pleura as well as MPM
  • In the authors' study, SKM9-2 antigen was negative in major non-mesothelial tumors, with a specificity of 99%
  • Later studies by other groups found focal, weak SKM9-2 staining in some lung squamous cell carcinomas and some ovarian carcinomas
  • In pleural effusions (Hiroshima et al.), mesothelioma cells were positive in 100% (41/41) of cases. Lung cancer cells and other cells, except ovarian carcinoma, were negative (0/34).
  • In the same effusion study, reactive (non-cancerous) mesothelial cells also showed strong membranous staining, in 77% (20/26)
  • The effusion study's authors recommended SKM9-2 antigen and claudin 4 to confirm mesothelial origin, and BAP1 and methylthioadenosine phosphorylase to confirm malignancy
  • Intelectin-1 protein was expressed in 88.5% of epithelioid-type MPM
  • Recognition by SKM9-2 required both HEG1 peptide sequences and two site-specific sialylated sugar modifications
  • The authors proposed SKM9-2 as a starting point for next-generation antibody drugs
• The authors' conclusion: The authors concluded that the SKM9-2 antigen is a sensitive tissue marker for various mesothelioma types, including MPM
• Limitations the authors state:
  • SKM9-2 does not recognize HEG1 in rodents, so organ safety is hard to guarantee in standard nonclinical studies
  • Tissue sections are only part of an organ, so it cannot be proven that the epitope is absent elsewhere in organs that express HEG1
  • The positive rate of SKM9-2 antigen in hepatocellular carcinoma has not been determined
  • The biological function of HEG1 and the effects of glycosylation on the epitope remain unclear

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Monoclonal Antibody, HEG1, Mesothelioma, Pleural Mesothelioma, Pleural Cavity, Lung Adenocarcinoma, Prognosis.

Related studies

• Identification of mesothelioma-specific sialylated epitope recognized with monoclonal antibody SKM9-2 in a mucin-like membrane protein HEG1 — R. Matsuura, H. Kaji, et al. (2018)
• First-in-human phase 1 of YS110, a monoclonal antibody directed against CD26 in advanced CD26-expressing cancers — E. Angevin, N. Isambert, et al. (2017)
• A novel PET imaging using ⁶⁴Cu-labeled monoclonal antibody against mesothelin commonly expressed on cancer cells — K. Kobayashi, T. Sasaki, et al. (2015)
• Establishment of Mouse Monoclonal Antibody LpMab-13 Against Human Podoplanin — S. Ogasawara, M.K. Kaneko, et al. (2016)
• Epitope Mapping of Monoclonal Antibody PMab-233 Against Tasmanian Devil Podoplanin — M. Sano, M.K. Kaneko, et al. (2019)
• Population pharmacokinetics and exposure-response relationship of amatuximab, an anti-mesothelin monoclonal antibody, in patients with malignant pleural mesothelioma and its application in dose selection — A. Gupta, Z. Hussein, et al. (2016)

Browse return to medical research.