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Development of a fully canine anti-canine CTLA4 monoclonal antibody for comparative translational research in dogs with spontaneous tumors
The immune checkpoint inhibitor (ICI) ipilimumab has revolutionized the treatment of patients with different cancer histologies, including melanoma, renal cell carcinoma, and non-small cell lung carcinoma. However, only a subset of patients shows dramatic clinical responses to treatment. Despite int...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8726733/ https://www.ncbi.nlm.nih.gov/pubmed/34856888 http://dx.doi.org/10.1080/19420862.2021.2004638 |
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author | Mason, Nicola J. Chester, Nicholas Xiong, Ailian Rotolo, Antonia Wu, Ying Yoshimoto, Sho Glassman, Patrick Gulendran, Gayathri Siegel, Don L. |
author_facet | Mason, Nicola J. Chester, Nicholas Xiong, Ailian Rotolo, Antonia Wu, Ying Yoshimoto, Sho Glassman, Patrick Gulendran, Gayathri Siegel, Don L. |
author_sort | Mason, Nicola J. |
collection | PubMed |
description | The immune checkpoint inhibitor (ICI) ipilimumab has revolutionized the treatment of patients with different cancer histologies, including melanoma, renal cell carcinoma, and non-small cell lung carcinoma. However, only a subset of patients shows dramatic clinical responses to treatment. Despite intense biomarker discovery efforts linked to clinical trials using CTLA4 checkpoint blockade, no single prognostic correlate has emerged as a valid predictor of outcome. Client-owned, immune competent, pet dogs develop spontaneous tumors that exhibit similar features to human cancers, including shared chromosome aberrations, molecular subtypes, immune signatures, tumor heterogeneity, metastatic behavior, and response to chemotherapy. As such, they represent a valuable parallel patient population in which to investigate novel predictive biomarkers and rational therapeutic ICI combinations. However, the lack of validated, non-immunogenic, canine ICIs for preclinical use hinders this comparative approach. To address this, fully canine single-chain variable fragments (scFvs) that bind canine CTLA4 were isolated from a comprehensive canine scFv phage display library. A lead candidate for clinical development was selected based on its subnanomolar binding affinity to canine CTLA4 and its ability to prevent CTLA4 binding to CD80/CD86 and promote T cell proliferation and effector function. In vivo mouse studies revealed pharmacokinetics similar to isotype control IgG with no evidence of short-term adverse effects. This work paves the way for in vivo analysis of the first fully canine, anti-canine CTLA4 antibody to promote anti-tumor immunity in dogs with immune-responsive cancers and provide an important comparative tool to investigate correlative biomarkers of response and mechanisms of resistance to CTLA4 checkpoint inhibition. |
format | Online Article Text |
id | pubmed-8726733 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-87267332022-01-05 Development of a fully canine anti-canine CTLA4 monoclonal antibody for comparative translational research in dogs with spontaneous tumors Mason, Nicola J. Chester, Nicholas Xiong, Ailian Rotolo, Antonia Wu, Ying Yoshimoto, Sho Glassman, Patrick Gulendran, Gayathri Siegel, Don L. MAbs Report The immune checkpoint inhibitor (ICI) ipilimumab has revolutionized the treatment of patients with different cancer histologies, including melanoma, renal cell carcinoma, and non-small cell lung carcinoma. However, only a subset of patients shows dramatic clinical responses to treatment. Despite intense biomarker discovery efforts linked to clinical trials using CTLA4 checkpoint blockade, no single prognostic correlate has emerged as a valid predictor of outcome. Client-owned, immune competent, pet dogs develop spontaneous tumors that exhibit similar features to human cancers, including shared chromosome aberrations, molecular subtypes, immune signatures, tumor heterogeneity, metastatic behavior, and response to chemotherapy. As such, they represent a valuable parallel patient population in which to investigate novel predictive biomarkers and rational therapeutic ICI combinations. However, the lack of validated, non-immunogenic, canine ICIs for preclinical use hinders this comparative approach. To address this, fully canine single-chain variable fragments (scFvs) that bind canine CTLA4 were isolated from a comprehensive canine scFv phage display library. A lead candidate for clinical development was selected based on its subnanomolar binding affinity to canine CTLA4 and its ability to prevent CTLA4 binding to CD80/CD86 and promote T cell proliferation and effector function. In vivo mouse studies revealed pharmacokinetics similar to isotype control IgG with no evidence of short-term adverse effects. This work paves the way for in vivo analysis of the first fully canine, anti-canine CTLA4 antibody to promote anti-tumor immunity in dogs with immune-responsive cancers and provide an important comparative tool to investigate correlative biomarkers of response and mechanisms of resistance to CTLA4 checkpoint inhibition. Taylor & Francis 2021-12-02 /pmc/articles/PMC8726733/ /pubmed/34856888 http://dx.doi.org/10.1080/19420862.2021.2004638 Text en © 2021 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. |
spellingShingle | Report Mason, Nicola J. Chester, Nicholas Xiong, Ailian Rotolo, Antonia Wu, Ying Yoshimoto, Sho Glassman, Patrick Gulendran, Gayathri Siegel, Don L. Development of a fully canine anti-canine CTLA4 monoclonal antibody for comparative translational research in dogs with spontaneous tumors |
title | Development of a fully canine anti-canine CTLA4 monoclonal antibody for comparative translational research in dogs with spontaneous tumors |
title_full | Development of a fully canine anti-canine CTLA4 monoclonal antibody for comparative translational research in dogs with spontaneous tumors |
title_fullStr | Development of a fully canine anti-canine CTLA4 monoclonal antibody for comparative translational research in dogs with spontaneous tumors |
title_full_unstemmed | Development of a fully canine anti-canine CTLA4 monoclonal antibody for comparative translational research in dogs with spontaneous tumors |
title_short | Development of a fully canine anti-canine CTLA4 monoclonal antibody for comparative translational research in dogs with spontaneous tumors |
title_sort | development of a fully canine anti-canine ctla4 monoclonal antibody for comparative translational research in dogs with spontaneous tumors |
topic | Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8726733/ https://www.ncbi.nlm.nih.gov/pubmed/34856888 http://dx.doi.org/10.1080/19420862.2021.2004638 |
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