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A novel non-agonist c-Met antibody drug conjugate with superior potency over a c-Met tyrosine kinase inhibitor in c-Met amplified and non-amplified cancers
c-Met is a well-characterized oncogene that is associated with poor prognosis in many solid tumor types. While responses to c-Met inhibitors have been observed in clinical trials, activity appears to be limited to those with MET gene amplifications or mutations. We developed a c-Met targeted antibod...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515515/ https://www.ncbi.nlm.nih.gov/pubmed/32192391 http://dx.doi.org/10.1080/15384047.2020.1737490 |
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author | Fujita, Ryo Blot, Vincent Wong, Eley Stewart, Christine Lieuw, Vincent Richardson, Robyn Banah, Ammar Villicana, Jose Timmer, Anjuli Coronella, Julia Newman, Roland Gymnopoulos, Marco |
author_facet | Fujita, Ryo Blot, Vincent Wong, Eley Stewart, Christine Lieuw, Vincent Richardson, Robyn Banah, Ammar Villicana, Jose Timmer, Anjuli Coronella, Julia Newman, Roland Gymnopoulos, Marco |
author_sort | Fujita, Ryo |
collection | PubMed |
description | c-Met is a well-characterized oncogene that is associated with poor prognosis in many solid tumor types. While responses to c-Met inhibitors have been observed in clinical trials, activity appears to be limited to those with MET gene amplifications or mutations. We developed a c-Met targeted antibody-drug conjugate (ADC) with preclinical activity in the absence of MET gene amplification or mutation, and activity even in the context of moderate protein expression. The ADC utilized a high-affinity c-Met antibody (P3D12), that induced c-Met degradation with minimal activation of c-Met signaling, or mitogenic effect. P3D12 was conjugated to the tubulin inhibitor toxin MMAF via a cleavable linker (vc-MMAF). P3D12-vc-MMAF demonstrated potent in vitro activity in c-Met protein-expressing cell lines regardless of MET gene amplification or mutation status, and retained activity in cell lines with medium-low c-Met protein expression. In contrast, the c-Met tyrosine kinase inhibitor (TKI) PHA-665752 slowed tumor cell growth in vitro only in the context of MET gene amplification or very high protein expression. This differential activity was even more marked in vivo. P3D12-vc-MMAF demonstrated robust inhibition of tumor growth in the MET gene amplified MKN-45 xenograft model, and similar results in H1975, which expresses moderate levels of wild type c-Met without genomic amplification. By comparison, the c-Met TKI, PHA-665752, demonstrated modest tumor growth inhibition in MKN-45, and no inhibition at all in H1975. Taken together, these data suggest that P3D12-vc-MMAF may have a superior clinical profile in treating c-Met positive malignancies in contrast to c-Met pathway inhibitors. |
format | Online Article Text |
id | pubmed-7515515 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-75155152020-10-01 A novel non-agonist c-Met antibody drug conjugate with superior potency over a c-Met tyrosine kinase inhibitor in c-Met amplified and non-amplified cancers Fujita, Ryo Blot, Vincent Wong, Eley Stewart, Christine Lieuw, Vincent Richardson, Robyn Banah, Ammar Villicana, Jose Timmer, Anjuli Coronella, Julia Newman, Roland Gymnopoulos, Marco Cancer Biol Ther Research Paper c-Met is a well-characterized oncogene that is associated with poor prognosis in many solid tumor types. While responses to c-Met inhibitors have been observed in clinical trials, activity appears to be limited to those with MET gene amplifications or mutations. We developed a c-Met targeted antibody-drug conjugate (ADC) with preclinical activity in the absence of MET gene amplification or mutation, and activity even in the context of moderate protein expression. The ADC utilized a high-affinity c-Met antibody (P3D12), that induced c-Met degradation with minimal activation of c-Met signaling, or mitogenic effect. P3D12 was conjugated to the tubulin inhibitor toxin MMAF via a cleavable linker (vc-MMAF). P3D12-vc-MMAF demonstrated potent in vitro activity in c-Met protein-expressing cell lines regardless of MET gene amplification or mutation status, and retained activity in cell lines with medium-low c-Met protein expression. In contrast, the c-Met tyrosine kinase inhibitor (TKI) PHA-665752 slowed tumor cell growth in vitro only in the context of MET gene amplification or very high protein expression. This differential activity was even more marked in vivo. P3D12-vc-MMAF demonstrated robust inhibition of tumor growth in the MET gene amplified MKN-45 xenograft model, and similar results in H1975, which expresses moderate levels of wild type c-Met without genomic amplification. By comparison, the c-Met TKI, PHA-665752, demonstrated modest tumor growth inhibition in MKN-45, and no inhibition at all in H1975. Taken together, these data suggest that P3D12-vc-MMAF may have a superior clinical profile in treating c-Met positive malignancies in contrast to c-Met pathway inhibitors. Taylor & Francis 2020-03-19 /pmc/articles/PMC7515515/ /pubmed/32192391 http://dx.doi.org/10.1080/15384047.2020.1737490 Text en © 2020 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. |
spellingShingle | Research Paper Fujita, Ryo Blot, Vincent Wong, Eley Stewart, Christine Lieuw, Vincent Richardson, Robyn Banah, Ammar Villicana, Jose Timmer, Anjuli Coronella, Julia Newman, Roland Gymnopoulos, Marco A novel non-agonist c-Met antibody drug conjugate with superior potency over a c-Met tyrosine kinase inhibitor in c-Met amplified and non-amplified cancers |
title | A novel non-agonist c-Met antibody drug conjugate with superior potency over a c-Met tyrosine kinase inhibitor in c-Met amplified and non-amplified cancers |
title_full | A novel non-agonist c-Met antibody drug conjugate with superior potency over a c-Met tyrosine kinase inhibitor in c-Met amplified and non-amplified cancers |
title_fullStr | A novel non-agonist c-Met antibody drug conjugate with superior potency over a c-Met tyrosine kinase inhibitor in c-Met amplified and non-amplified cancers |
title_full_unstemmed | A novel non-agonist c-Met antibody drug conjugate with superior potency over a c-Met tyrosine kinase inhibitor in c-Met amplified and non-amplified cancers |
title_short | A novel non-agonist c-Met antibody drug conjugate with superior potency over a c-Met tyrosine kinase inhibitor in c-Met amplified and non-amplified cancers |
title_sort | novel non-agonist c-met antibody drug conjugate with superior potency over a c-met tyrosine kinase inhibitor in c-met amplified and non-amplified cancers |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515515/ https://www.ncbi.nlm.nih.gov/pubmed/32192391 http://dx.doi.org/10.1080/15384047.2020.1737490 |
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