Health Science Reviews

By Samantha Levetan

In the realm of immunotherapy, the hunt for a suitable target never wavers. The
target of every oncology researcher’s dreams? Differentially overexpressed on
cancer cells and druggable – not such an abundant find.

Enter mesothelin (MSLN), a cell-surface protein whose expression was found to be
upregulated in ovarian cancers. Further studies showed it is also overexpressed in
diverse tumour types ranging from cervical carcinomas to haematological
malignancies.

MSLN certainly meets the first criterium of differential overexpression. And
preliminary studies with anti-MSLN immunotoxins as well as CAR T cells showed
promise. But MSLN is in fact no perfect target – a phenomenon known as proteolytic
shedding actually makes it rather elusive.

That’s right – if you thought shedding of your pet hairs onto clothing or furniture was
irritating enough, cell-surface receptor shedding too poses a challenge to
immunotherapy researchers. Proteolytic shedding results in the release of soluble
MSLN-related peptides (SMRP), leaving behind a truncated membrane-bound
fragment on the cell surface. The extracellular environment contains various
proteases that can cleave MSLN at different sites, leading to heterogeneous
shedding patterns.

That certainly poses a challenge to researchers – avoiding accidental targeting of the
shed peptides as opposed to the membrane-bound fragments key to tumour
targeting, is paramount to the success of anti-cancer therapies.

To tackle this, Liu et al. (2024) developed a clever workaround: an antibody called
15B6, designed to bind to the truncated part of MSLN left on the cell surface after
shedding. This meant the antibody could ignore the SMRPs and find its intended
target. This positions 15B6 as a promising antibody for use in other
immunotherapeutic strategies such as BiTEs and antibody-drug conjugates.

Before you write off MSLN shedding as being about as useful as stray pet hairs, I
implore you to think twice. SMRPs can be captured by liquid biopsy and utilised as a
biomarker for detection of malignant mesotheliomas and an indicator of tumour
burden. This makes it useful for diagnostics and monitoring of disease progression
or response to treatment.

MSLN shedding can act as both a hindrance to targeted therapies and a useful
biomarker – it all depends on which side of the coin you look at. And with recent
advances in developing anti-shedding MSLN antibodies, MSLN might just acquire
dual utility, making shedding not so much of a nuisance after all.

Bibliography:
Liu, X. F., Onda, M., Schlomer, J., Bassel, L., Kozlov, S., Tai, C.-H., Zhou, Q., Liu, W.,
Tsao, H.-E., Hassan, R., Ho, M., & Pastan, I. (2024). Tumor resistance to anti-
mesothelin CAR-T cells caused by binding to shed mesothelin is overcome by
targeting a juxtamembrane epitope. Proceedings of the National Academy of
Sciences, 121(4). https://doi.org/10.1073/pnas.2317283121

Faust, J. R., Hamill, D., Kolb, E. A., Gopalakrishnapillai, A., & Barwe, S. P. (2022).
Mesothelin: An Immunotherapeutic Target beyond Solid Tumors. Cancers, 14(6), 1550. https://doi.org/10.3390/cancers14061550

Lv, J., & Li, P. (2019). Mesothelin as a biomarker for targeted therapy. Biomarker
Research, 7(1), 18. https://doi.org/10.1186/s40364-019-0169-8