Document Type
Article
Publication Date
2-1-2020
Publication Title
Biotechnology and Bioengineering
Abstract
Mesothelin is a protein expressed at high levels on the cell surface in a variety of cancers, with limited expression in healthy tissues. The presence of mesothelin on tumor tissue correlates with increased invasion and metastasis, and resistance to traditional chemotherapies, through mechanisms that remain poorly understood. Molecules that specifically recognize mesothelin and interrupt its contribution to tumor progression have significant potential for targeted therapy and targeted drug delivery applications. A number of mesothelin-targeting therapies are in preclinical and clinical development, although none are currently approved for routine clinical use. In this work, we report the development of a mesothelin-targeting protein based on the fibronectin type-III non-antibody protein scaffold, which offers opportunities for applications where antibodies have limitations. We engineered protein variants that bind mesothelin with high affinity and selectively initiate apoptosis in tumor cells expressing mesothelin. Interestingly, apoptosis does not occur through a caspase-mediated pathway and does not require downregulation of cell-surface mesothelin, suggesting a currently unknown pathway through which mesothelin contributes to cancer progression. Importantly, simultaneous treatment with mesothelin-binding protein and chemotherapeutic mitomycin C had a greater cytotoxic effect on mesothelin-positive cells compared to either molecule alone, underscoring the potential for combination therapy including biologics targeting mesothelin.
Keywords
cancer, combination therapy, mesothelin, protein engineering, targeted therapy
Volume
117
Issue
2
First Page
330
Last Page
341
DOI
10.1002/bit.27204
ISSN
00063592
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Rights
Licensed to Smith College and distributed CC-BY under the Smith College Faculty Open Access Policy
Recommended Citation
Sirois, Allison R.; Deny, Daniela A.; Li, Yanxuan; Fall, Yacine D.; and Moore, Sarah J., "Engineered Fn3 Protein has Targeted Therapeutic Effect on Mesothelin-Expressing Cancer Cells and Increases Tumor Cell Sensitivity to Chemotherapy" (2020). Engineering: Faculty Publications, Smith College, Northampton, MA.
https://scholarworks.smith.edu/egr_facpubs/57
Comments
Peer reviewed accepted manuscript.