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Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody
IMAB362/Zolbetuximab, a first-in-class IgG1 antibody directed against the cancer-associated gastric-lineage marker CLDN18.2, has recently been reported to have met its primary endpoint in two phase 3 trials as a first-line treatment in combination with standard of care chemotherapy in CLDN18.2-posit...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10583639/ https://www.ncbi.nlm.nih.gov/pubmed/37860278 http://dx.doi.org/10.1080/2162402X.2023.2255041 |
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author | Bähr-Mahmud, Hayat Ellinghaus, Ursula Stadler, Christiane R. Fischer, Leyla Lindemann, Claudia Chaturvedi, Anuhar Diekmann, Jan Wöll, Stefan Biermann, Imke Hebich, Bernhard Scharf, Caroline Siefke, Manuela Roth, Alexandra S. Rao, Martin Brettschneider, Kerstin Ewen, Eva-Maria Şahin, Uğur Türeci, Özlem |
author_facet | Bähr-Mahmud, Hayat Ellinghaus, Ursula Stadler, Christiane R. Fischer, Leyla Lindemann, Claudia Chaturvedi, Anuhar Diekmann, Jan Wöll, Stefan Biermann, Imke Hebich, Bernhard Scharf, Caroline Siefke, Manuela Roth, Alexandra S. Rao, Martin Brettschneider, Kerstin Ewen, Eva-Maria Şahin, Uğur Türeci, Özlem |
author_sort | Bähr-Mahmud, Hayat |
collection | PubMed |
description | IMAB362/Zolbetuximab, a first-in-class IgG1 antibody directed against the cancer-associated gastric-lineage marker CLDN18.2, has recently been reported to have met its primary endpoint in two phase 3 trials as a first-line treatment in combination with standard of care chemotherapy in CLDN18.2-positive Her2 negative advanced gastric cancer. Here we characterize the preclinical pharmacology of BNT141, a nucleoside-modified RNA therapeutic encoding the sequence of IMAB362/Zolbetuximab, formulated in lipid nanoparticles (LNP) for liver uptake. We show that the mRNA-encoded antibody displays a stable pharmacokinetic profile in preclinical animal models, mediates CLDN18.2-restricted cytotoxicity comparable to IMAB362 recombinant protein and inhibits human tumor xenograft growth in immunocompromised mice. BNT141 administration did not perpetrate mortality, clinical signs of toxicity, or gastric pathology in animal studies. A phase 1/2 clinical trial with BNT141 mRNA-LNP has been initiated in advanced CLDN18.2-expressing solid cancers (NCT04683939). |
format | Online Article Text |
id | pubmed-10583639 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-105836392023-10-19 Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody Bähr-Mahmud, Hayat Ellinghaus, Ursula Stadler, Christiane R. Fischer, Leyla Lindemann, Claudia Chaturvedi, Anuhar Diekmann, Jan Wöll, Stefan Biermann, Imke Hebich, Bernhard Scharf, Caroline Siefke, Manuela Roth, Alexandra S. Rao, Martin Brettschneider, Kerstin Ewen, Eva-Maria Şahin, Uğur Türeci, Özlem Oncoimmunology Brief Report IMAB362/Zolbetuximab, a first-in-class IgG1 antibody directed against the cancer-associated gastric-lineage marker CLDN18.2, has recently been reported to have met its primary endpoint in two phase 3 trials as a first-line treatment in combination with standard of care chemotherapy in CLDN18.2-positive Her2 negative advanced gastric cancer. Here we characterize the preclinical pharmacology of BNT141, a nucleoside-modified RNA therapeutic encoding the sequence of IMAB362/Zolbetuximab, formulated in lipid nanoparticles (LNP) for liver uptake. We show that the mRNA-encoded antibody displays a stable pharmacokinetic profile in preclinical animal models, mediates CLDN18.2-restricted cytotoxicity comparable to IMAB362 recombinant protein and inhibits human tumor xenograft growth in immunocompromised mice. BNT141 administration did not perpetrate mortality, clinical signs of toxicity, or gastric pathology in animal studies. A phase 1/2 clinical trial with BNT141 mRNA-LNP has been initiated in advanced CLDN18.2-expressing solid cancers (NCT04683939). Taylor & Francis 2023-10-16 /pmc/articles/PMC10583639/ /pubmed/37860278 http://dx.doi.org/10.1080/2162402X.2023.2255041 Text en © 2023 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent. |
spellingShingle | Brief Report Bähr-Mahmud, Hayat Ellinghaus, Ursula Stadler, Christiane R. Fischer, Leyla Lindemann, Claudia Chaturvedi, Anuhar Diekmann, Jan Wöll, Stefan Biermann, Imke Hebich, Bernhard Scharf, Caroline Siefke, Manuela Roth, Alexandra S. Rao, Martin Brettschneider, Kerstin Ewen, Eva-Maria Şahin, Uğur Türeci, Özlem Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody |
title | Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody |
title_full | Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody |
title_fullStr | Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody |
title_full_unstemmed | Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody |
title_short | Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody |
title_sort | preclinical characterization of an mrna-encoded anti-claudin 18.2 antibody |
topic | Brief Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10583639/ https://www.ncbi.nlm.nih.gov/pubmed/37860278 http://dx.doi.org/10.1080/2162402X.2023.2255041 |
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