Possible Therapeutic Utility of anti-Cell Adhesion Molecule 1 Antibodies for Malignant Pleural Mesothelioma

Our plain-English summary of Possible Therapeutic Utility of anti-Cell Adhesion Molecule 1 Antibodies for Malignant Pleural Mesothelioma, by M. Hagiyama, T. Mimae, A. Wada, et al (Frontiers in Cell and Developmental Biology, 2022).

The study

• Authors: M. Hagiyama, T. Mimae, A. Wada, F. Takeuchi, A. Yoneshige, T. Inoue, N. Kotoku, H. Hamada, Y. Sekido, M. Okada, A. Ito
• Journal: Frontiers in Cell and Developmental Biology
• Published: 2022;10:945007
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a highly aggressive malignant tumor, and the effective therapeutic drugs are limited. Thus, the establishment of novel therapeutic method is desired. Considerable proportion of MPMs are shown to express cell adhesion molecule 1 (CADM1), and to use CADM1 to bind to and proliferate on the pleural mesothelial surface, suggesting that CADM1 is a possible therapeutic target. Here, anti-CADM1 ectodomain chicken monoclonal antibodies, 3E1 and 9D2, were examined for their possible therapeutic utility. The full-length form of CADM1 was expressed in eight out of twelve human MPM cell lines. MPM cell lines were cultured on a confluent monolayer of mesothelial MeT-5A cells in the presence of 9D2, the neutralizing antibody. 9D2 suppressed the cell growth of CADM1-positive MPM cells with the loss and aggregation of CADM1 molecules on the MPM cell membrane, but not of CADM1-negative MPM cells. Co-addition of 3E1, lacking the neutralizing action, enhanced the growth-suppressive effect of 9D2. The two antibodies were tested as drug delivery vectors. 3E1 was converted into a humanized antibody (h3E1) and conjugated with monomethyl auristatin E (MMAE), a tubulin polymerization inhibitor. When the resulting h3E1-MMAE antibody-drug conjugate (ADC) was added to the standard cultures of CADM1-positive MPM cells, it suppressed the cell growth in a dose-dependent manner. Co-addition of 9D2 enhanced the growth-suppressive effect of h3E1-MMAE ADC. Anti-CADM1 ectodomain antibodies were suggested to serve as both antibody drugs and drug vectors in the treatment of MPM.

Copyright © 2022 Hagiyama, Mimae, Wada, Takeuchi, Yoneshige, Inoue, Kotoku, Hamada, Sekido, Okada and Ito.

In plain English

This was a laboratory study of two chicken monoclonal antibodies against the ectodomain of cell adhesion molecule 1 (CADM1), 9D2 (neutralizing) and 3E1, in human malignant pleural mesothelioma (MPM) cell lines. Western blotting of eleven MPM lines, a CADM1-transfected subline (MESO-1-CADM1) and the mesothelial line MeT-5A detected the full-length CADM1 in 8 cell lines; MeT-5A lacked it but expressed CADM4. Sheets of MPM cells were grown on MeT-5A monolayers to mimic plaque growth on pleura. With control IgY or 3E1, MPM cells grew over 2 days at rates of 1.47–2.26; 9D2 reduced growth of CADM1-positive lines (MESO-1-CADM1, NCI-H28, NCI-H2052, MESO-14) but not of MESO-1, and 9D2 together with 3E1 gave growth rates of 0.70 to 0.90 in those four CADM1-positive lines. In TUNEL assays done only in MESO-14 and NCI-H2052, 9D2 with 3E1 produced about 4–8% TUNEL-positive cells. A humanized 3E1 conjugated to monomethyl auristatin E lowered viability dose-dependently (IC50 3.078 μg/ml for MESO-1-CADM1; with 9D2 added, 0.970 μg/ml for MESO-1-CADM1 and 1.054 μg/ml for MESO-14) and was substantially ineffective on MESO-1. The authors concluded these antibodies could serve as antibody drugs and drug vectors.

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: In vitro laboratory study using human mesothelioma cell lines (Western blotting, antibody treatment in a coculture model, apoptosis assay, antibody-drug conjugate viability assay)
• Who was studied: Eleven human malignant pleural mesothelioma cell lines, one CADM1-transfected subline (MESO-1-CADM1) and the mesothelial cell line MeT-5A; no human participants
• Exposure: Anti-CADM1 ectodomain chicken monoclonal antibodies 9D2 and 3E1 (1.0 μg/ml each in coculture), and a humanized 3E1 conjugated to monomethyl auristatin E (h3E1–MMAE antibody-drug conjugate) at 0.1, 0.5, 1 and 5 μg/ml
• Main results:
  • Full-length CADM1 was detected in 8 of the cell lines blotted; MeT-5A mesothelial cells did not express it but expressed CADM4
  • With control IgY or 3E1, MPM cells on MeT-5A monolayers grew over 2 days at rates of 1.47–2.26; 9D2 reduced growth of CADM1-positive lines but not of MESO-1
  • Co-addition of 9D2 and 3E1 brought growth rates below 1.0 (0.70 to 0.90) in the four CADM1-positive lines, with no effect on MESO-1
  • In MESO-14 and NCI-H2052 cocultures only, 9D2 plus 3E1 produced about 4–8% TUNEL-positive MPM cells, versus substantially none with control IgY
  • h3E1–MMAE ADC alone reduced viability of CADM1-positive MPM cells by about 30–50% dose-dependently, IC50 3.078 μg/ml for MESO-1-CADM1
  • Adding 9D2 lowered viability below 30%, with IC50 0.970 μg/ml for MESO-1-CADM1 and 1.054 μg/ml for MESO-14; the ADC was substantially ineffective on CADM1-negative MESO-1
• The authors' conclusion: The authors concluded that the study highlights a role of cell adhesion in MPM growth and that anti-CADM1 ectodomain antibodies could serve as a new treatment modality, as both antibody drugs and drug vectors, with further characterization needed
• Limitations the authors state:
  • The authors state they do not yet know biological or clinical differences between CADM1-positive and CADM1-negative MPMs
  • Work remained at the cell-culture stage; humanized 9D2 and animal experiments were still planned

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Monoclonal Antibody, MeT-5A Cells.

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