Selection, characterization and in vivo evaluation of novel CD44v6-targeting antibodies for targeted molecular radiotherapy
Abstract Molecular radiotherapy combines the advantages of systemic administration of highly specific antibodies or peptides and the localized potency of ionizing radiation. A potential target for molecular radiotherapy is the cell surface antigen CD44v6, which is overexpressed in numerous cancers,...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-11-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-47891-2 |
| _version_ | 1797453010754863104 |
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| author | A. C. L. Mortensen H. Berglund L. Segerström M. Walle C. Hofström H. Persson P.-Å. Nygren J. Nilvebrant F. Y. Frejd M. Nestor |
| author_facet | A. C. L. Mortensen H. Berglund L. Segerström M. Walle C. Hofström H. Persson P.-Å. Nygren J. Nilvebrant F. Y. Frejd M. Nestor |
| author_sort | A. C. L. Mortensen |
| collection | DOAJ |
| description | Abstract Molecular radiotherapy combines the advantages of systemic administration of highly specific antibodies or peptides and the localized potency of ionizing radiation. A potential target for molecular radiotherapy is the cell surface antigen CD44v6, which is overexpressed in numerous cancers, with limited expression in normal tissues. The aim of the present study was to generate and characterize a panel of human anti-CD44v6 antibodies and identify a suitable candidate for future use in molecular radiotherapy of CD44v6-expressing cancers. Binders were first isolated from large synthetic phage display libraries containing human scFv and Fab antibody fragments. The antibodies were extensively analyzed through in vitro investigations of binding kinetics, affinity, off-target binding, and cell binding. Lead candidates were further subjected to in vivo biodistribution studies in mice bearing anaplastic thyroid cancer xenografts that express high levels of CD44v6. Additionally, antigen-dependent tumor uptake of the lead candidate was verified in additional xenograft models with varying levels of target expression. Interestingly, although only small differences were observed among the top antibody candidates in vitro, significant differences in tumor uptake and retention were uncovered in in vivo experiments. A high-affinity anti-CD44v6 lead drug candidate was identified, mAb UU-40, which exhibited favorable target binding properties and in vivo distribution. In conclusion, a panel of human anti-CD44v6 antibodies was successfully generated and characterized in this study. Through comprehensive evaluation, mAb UU-40 was identified as a promising lead candidate for future molecular radiotherapy of CD44v6-expressing cancers due to its high affinity, excellent target binding properties, and desirable in vivo distribution characteristics. |
| first_indexed | 2024-03-09T15:16:44Z |
| format | Article |
| id | doaj.art-9827a0b4e48c4d1f889a1a09dbe78849 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-09T15:16:44Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-9827a0b4e48c4d1f889a1a09dbe788492023-11-26T13:03:31ZengNature PortfolioScientific Reports2045-23222023-11-0113111110.1038/s41598-023-47891-2Selection, characterization and in vivo evaluation of novel CD44v6-targeting antibodies for targeted molecular radiotherapyA. C. L. Mortensen0H. Berglund1L. Segerström2M. Walle3C. Hofström4H. Persson5P.-Å. Nygren6J. Nilvebrant7F. Y. Frejd8M. Nestor9Department of Molecular Medicine and Surgery, Karolinska InstitutetDepartment of Immunology, Genetics and Pathology, Science for Life Laboratory (SciLifeLab), Uppsala UniversityDepartment of Immunology, Genetics and Pathology, Science for Life Laboratory (SciLifeLab), Uppsala UniversityDrug Discovery and Development Platform, Science for Life Laboratory (SciLifeLab)Drug Discovery and Development Platform, Science for Life Laboratory (SciLifeLab)Drug Discovery and Development Platform, Science for Life Laboratory (SciLifeLab)Drug Discovery and Development Platform, Science for Life Laboratory (SciLifeLab)Department of Protein Science, KTH Royal Institute of TechnologyDepartment of Immunology, Genetics and Pathology, Science for Life Laboratory (SciLifeLab), Uppsala UniversityDepartment of Immunology, Genetics and Pathology, Science for Life Laboratory (SciLifeLab), Uppsala UniversityAbstract Molecular radiotherapy combines the advantages of systemic administration of highly specific antibodies or peptides and the localized potency of ionizing radiation. A potential target for molecular radiotherapy is the cell surface antigen CD44v6, which is overexpressed in numerous cancers, with limited expression in normal tissues. The aim of the present study was to generate and characterize a panel of human anti-CD44v6 antibodies and identify a suitable candidate for future use in molecular radiotherapy of CD44v6-expressing cancers. Binders were first isolated from large synthetic phage display libraries containing human scFv and Fab antibody fragments. The antibodies were extensively analyzed through in vitro investigations of binding kinetics, affinity, off-target binding, and cell binding. Lead candidates were further subjected to in vivo biodistribution studies in mice bearing anaplastic thyroid cancer xenografts that express high levels of CD44v6. Additionally, antigen-dependent tumor uptake of the lead candidate was verified in additional xenograft models with varying levels of target expression. Interestingly, although only small differences were observed among the top antibody candidates in vitro, significant differences in tumor uptake and retention were uncovered in in vivo experiments. A high-affinity anti-CD44v6 lead drug candidate was identified, mAb UU-40, which exhibited favorable target binding properties and in vivo distribution. In conclusion, a panel of human anti-CD44v6 antibodies was successfully generated and characterized in this study. Through comprehensive evaluation, mAb UU-40 was identified as a promising lead candidate for future molecular radiotherapy of CD44v6-expressing cancers due to its high affinity, excellent target binding properties, and desirable in vivo distribution characteristics.https://doi.org/10.1038/s41598-023-47891-2 |
| spellingShingle | A. C. L. Mortensen H. Berglund L. Segerström M. Walle C. Hofström H. Persson P.-Å. Nygren J. Nilvebrant F. Y. Frejd M. Nestor Selection, characterization and in vivo evaluation of novel CD44v6-targeting antibodies for targeted molecular radiotherapy Scientific Reports |
| title | Selection, characterization and in vivo evaluation of novel CD44v6-targeting antibodies for targeted molecular radiotherapy |
| title_full | Selection, characterization and in vivo evaluation of novel CD44v6-targeting antibodies for targeted molecular radiotherapy |
| title_fullStr | Selection, characterization and in vivo evaluation of novel CD44v6-targeting antibodies for targeted molecular radiotherapy |
| title_full_unstemmed | Selection, characterization and in vivo evaluation of novel CD44v6-targeting antibodies for targeted molecular radiotherapy |
| title_short | Selection, characterization and in vivo evaluation of novel CD44v6-targeting antibodies for targeted molecular radiotherapy |
| title_sort | selection characterization and in vivo evaluation of novel cd44v6 targeting antibodies for targeted molecular radiotherapy |
| url | https://doi.org/10.1038/s41598-023-47891-2 |
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