The 2EF Antibody Targets a Unique N-Terminal Epitope of Trop-2 and Enhances the In Vivo Activity of the Cancer-Selective 2G10 Antibody
Trop-2 proteolytic processing in cancer cells exposes epitopes that were specifically targeted by the 2G10 antibody. We sought additional recognition of Trop-2 within difficult-to-reach, densely packed tumor sites. Trop-2 deletion mutants were employed in immunization and screening procedures, and t...
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MDPI AG
2023-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/14/3721 |
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| author | Emanuela Guerra Marco Trerotola Valeria Relli Rossano Lattanzio Martina Ceci Khouloud Boujnah Ludovica Pantalone Roberta Di Pietro Manuela Iezzi Nicola Tinari Saverio Alberti |
| author_facet | Emanuela Guerra Marco Trerotola Valeria Relli Rossano Lattanzio Martina Ceci Khouloud Boujnah Ludovica Pantalone Roberta Di Pietro Manuela Iezzi Nicola Tinari Saverio Alberti |
| author_sort | Emanuela Guerra |
| collection | DOAJ |
| description | Trop-2 proteolytic processing in cancer cells exposes epitopes that were specifically targeted by the 2G10 antibody. We sought additional recognition of Trop-2 within difficult-to-reach, densely packed tumor sites. Trop-2 deletion mutants were employed in immunization and screening procedures, and these led to the recognition of a novel epitope in the N-terminal region of Trop-2, by the 2EF antibody. The 2EF mAb was shown to bind Trop-2 at cell–cell junctions in MCF-7 breast cancer cells, and in deeply seated sites in prostate cancer, that were inaccessible to benchmark anti-Trop-2 antibodies. The 2EF antibody was shown to inhibit the growth of HT29 colon tumor cells in vitro, with the highest activity at high cell density. In vivo, 2EF showed anticancer activity against SKOv3 ovarian, Colo205, HT29, HCT116 colon and DU-145 prostate tumors, with the highest impact on densely packed tumor sites, whereby 2EF outcompeted benchmark anti-Trop-2 antibodies. Given the different recognition modes of Trop-2 by 2EF and 2G10, we hypothesized the effective interaction of the two mAb in vivo. The 2EF mAb was indeed demonstrated to enhance the activity of 2G10 against tumor xenotransplants, opening novel avenues for Trop-2-targeted therapy. We humanized 2EF by state-of-the-art CDR grafting/re-modeling, yielding the Hu2EF for therapy of Trop-2-expressing tumors in patients. |
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| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T01:12:43Z |
| publishDate | 2023-07-01 |
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| record_format | Article |
| series | Cancers |
| spelling | doaj.art-80b4661eb3ff4a99ba1248e2057e57692023-11-18T18:43:13ZengMDPI AGCancers2072-66942023-07-011514372110.3390/cancers15143721The 2EF Antibody Targets a Unique N-Terminal Epitope of Trop-2 and Enhances the In Vivo Activity of the Cancer-Selective 2G10 AntibodyEmanuela Guerra0Marco Trerotola1Valeria Relli2Rossano Lattanzio3Martina Ceci4Khouloud Boujnah5Ludovica Pantalone6Roberta Di Pietro7Manuela Iezzi8Nicola Tinari9Saverio Alberti10Laboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, ItalyLaboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, ItalyLaboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, ItalyLaboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, ItalyLaboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, ItalyUnit of Medical Genetics, Department of Biomedical Sciences—BIOMORF, University of Messina, 98125 Messina, ItalyLaboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, ItalyDepartment of Medicine and Aging Sciences, Section of Biomorphology, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, ItalyDepartment of Neurosciences, Imaging and Clinical Sciences, Center for Advanced Studies and Technnology (CAST), G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, ItalyDepartment of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, ItalyUnit of Medical Genetics, Department of Biomedical Sciences—BIOMORF, University of Messina, 98125 Messina, ItalyTrop-2 proteolytic processing in cancer cells exposes epitopes that were specifically targeted by the 2G10 antibody. We sought additional recognition of Trop-2 within difficult-to-reach, densely packed tumor sites. Trop-2 deletion mutants were employed in immunization and screening procedures, and these led to the recognition of a novel epitope in the N-terminal region of Trop-2, by the 2EF antibody. The 2EF mAb was shown to bind Trop-2 at cell–cell junctions in MCF-7 breast cancer cells, and in deeply seated sites in prostate cancer, that were inaccessible to benchmark anti-Trop-2 antibodies. The 2EF antibody was shown to inhibit the growth of HT29 colon tumor cells in vitro, with the highest activity at high cell density. In vivo, 2EF showed anticancer activity against SKOv3 ovarian, Colo205, HT29, HCT116 colon and DU-145 prostate tumors, with the highest impact on densely packed tumor sites, whereby 2EF outcompeted benchmark anti-Trop-2 antibodies. Given the different recognition modes of Trop-2 by 2EF and 2G10, we hypothesized the effective interaction of the two mAb in vivo. The 2EF mAb was indeed demonstrated to enhance the activity of 2G10 against tumor xenotransplants, opening novel avenues for Trop-2-targeted therapy. We humanized 2EF by state-of-the-art CDR grafting/re-modeling, yielding the Hu2EF for therapy of Trop-2-expressing tumors in patients.https://www.mdpi.com/2072-6694/15/14/3721Trop-2cancer vulnerabilityprecision medicinetarget epitopes |
| spellingShingle | Emanuela Guerra Marco Trerotola Valeria Relli Rossano Lattanzio Martina Ceci Khouloud Boujnah Ludovica Pantalone Roberta Di Pietro Manuela Iezzi Nicola Tinari Saverio Alberti The 2EF Antibody Targets a Unique N-Terminal Epitope of Trop-2 and Enhances the In Vivo Activity of the Cancer-Selective 2G10 Antibody Cancers Trop-2 cancer vulnerability precision medicine target epitopes |
| title | The 2EF Antibody Targets a Unique N-Terminal Epitope of Trop-2 and Enhances the In Vivo Activity of the Cancer-Selective 2G10 Antibody |
| title_full | The 2EF Antibody Targets a Unique N-Terminal Epitope of Trop-2 and Enhances the In Vivo Activity of the Cancer-Selective 2G10 Antibody |
| title_fullStr | The 2EF Antibody Targets a Unique N-Terminal Epitope of Trop-2 and Enhances the In Vivo Activity of the Cancer-Selective 2G10 Antibody |
| title_full_unstemmed | The 2EF Antibody Targets a Unique N-Terminal Epitope of Trop-2 and Enhances the In Vivo Activity of the Cancer-Selective 2G10 Antibody |
| title_short | The 2EF Antibody Targets a Unique N-Terminal Epitope of Trop-2 and Enhances the In Vivo Activity of the Cancer-Selective 2G10 Antibody |
| title_sort | 2ef antibody targets a unique n terminal epitope of trop 2 and enhances the in vivo activity of the cancer selective 2g10 antibody |
| topic | Trop-2 cancer vulnerability precision medicine target epitopes |
| url | https://www.mdpi.com/2072-6694/15/14/3721 |
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