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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2021-01-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2021.2004638 |
| _version_ | 1811314389841608704 |
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| author | Nicola J. Mason Nicholas Chester Ailian Xiong Antonia Rotolo Ying Wu Sho Yoshimoto Patrick Glassman Gayathri Gulendran Don L. Siegel |
| author_facet | Nicola J. Mason Nicholas Chester Ailian Xiong Antonia Rotolo Ying Wu Sho Yoshimoto Patrick Glassman Gayathri Gulendran Don L. Siegel |
| author_sort | Nicola J. Mason |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-13T11:10:54Z |
| format | Article |
| id | doaj.art-3d1a06698fe447c889e66b51ed9b5518 |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-04-13T11:10:54Z |
| publishDate | 2021-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-3d1a06698fe447c889e66b51ed9b55182022-12-22T02:49:07ZengTaylor & Francis GroupmAbs1942-08621942-08702021-01-0113110.1080/19420862.2021.2004638Development of a fully canine anti-canine CTLA4 monoclonal antibody for comparative translational research in dogs with spontaneous tumorsNicola J. Mason0Nicholas Chester1Ailian Xiong2Antonia Rotolo3Ying Wu4Sho Yoshimoto5Patrick Glassman6Gayathri Gulendran7Don L. Siegel8Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USAVetigenics LLC, Philadelphia, PA, USADepartment of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Immunobiology, Yale University, New Haven, CT, USADepartment of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA, USACenter for Cellular Immunotherapy, Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA, USAThe 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.https://www.tandfonline.com/doi/10.1080/19420862.2021.2004638Checkpoint inhibitorcanineCTLA4large animal modelmonoclonal antibodysingle chain variable fragment |
| spellingShingle | Nicola J. Mason Nicholas Chester Ailian Xiong Antonia Rotolo Ying Wu Sho Yoshimoto Patrick Glassman Gayathri Gulendran Don L. Siegel Development of a fully canine anti-canine CTLA4 monoclonal antibody for comparative translational research in dogs with spontaneous tumors mAbs Checkpoint inhibitor canine CTLA4 large animal model monoclonal antibody single chain variable fragment |
| 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 | Checkpoint inhibitor canine CTLA4 large animal model monoclonal antibody single chain variable fragment |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2021.2004638 |
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