Development and pharmacokinetic assessment of a fully canine anti-PD-1 monoclonal antibody for comparative translational research in dogs with spontaneous tumors
PD-1 checkpoint inhibitors have 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 show a dramatic clinical response to treatment. Despite intense biomarker discove...
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Taylor & Francis Group
2023-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2023.2287250 |
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| author | Sho Yoshimoto Nicholas Chester Ailian Xiong Enrico Radaelli Hong Wang Marc Brillantes Gayathri Gulendran Patrick Glassman Don L. Siegel Nicola J. Mason |
| author_facet | Sho Yoshimoto Nicholas Chester Ailian Xiong Enrico Radaelli Hong Wang Marc Brillantes Gayathri Gulendran Patrick Glassman Don L. Siegel Nicola J. Mason |
| author_sort | Sho Yoshimoto |
| collection | DOAJ |
| description | PD-1 checkpoint inhibitors have 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 show a dramatic clinical response to treatment. Despite intense biomarker discovery efforts, no single robust, prognostic correlation has emerged as a valid outcome predictor. Immune competent, pet dogs develop spontaneous tumors that share similar features to human cancers including chromosome aberrations, molecular subtypes, immune signatures, tumor heterogeneity, metastatic behavior, and chemotherapeutic response. As such, they represent a valuable parallel patient population in which to investigate predictive biomarkers of checkpoint inhibition. However, the lack of a validated, non-immunogenic, canine anti-PD-1 antibody for pre-clinical use hinders this comparative approach and prevents potential clinical benefits of PD-1 blockade being realized in the veterinary clinic. To address this, fully canine single-chain variable fragments (scFvs) that bind canine (c)PD-1 were isolated from a comprehensive canine scFv phage display library. Lead candidates were identified that bound with high affinity to cPD-1 and inhibited its interaction with canine PD-L1 (cPD-L1). The lead scFv candidate re-formatted into a fully canine IgGD reversed the inhibitory effects of cPD-1:cPD-L1 interaction on canine chimeric antigen receptor (CAR) T cell function. In vivo administration showed no toxicity and revealed favorable pharmacokinetics for a reasonable dosing schedule. These results pave the way for clinical trials with anti-cPD-1 in canine cancer patients to investigate predictive biomarkers and combination regimens to inform human clinical trials and bring a promising checkpoint inhibitor into the veterinary armamentarium. |
| format | Article |
| id | doaj-art-e2cc3ba3c4cc456f979a67ebfed7ed7f |
| institution | DOAJ |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-e2cc3ba3c4cc456f979a67ebfed7ed7f2025-08-20T03:15:16ZengTaylor & Francis GroupmAbs1942-08621942-08702023-12-0115110.1080/19420862.2023.2287250Development and pharmacokinetic assessment of a fully canine anti-PD-1 monoclonal antibody for comparative translational research in dogs with spontaneous tumorsSho Yoshimoto0Nicholas Chester1Ailian Xiong2Enrico Radaelli3Hong Wang4Marc Brillantes5Gayathri Gulendran6Patrick Glassman7Don L. Siegel8Nicola J. Mason9Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USAVetigenics LLC, B-Labs, Cira Center, Philadelphia, PA, USADepartment of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USAVetigenics LLC, B-Labs, Cira Center, Philadelphia, PA, USAVetigenics LLC, B-Labs, Cira Center, Philadelphia, PA, USACenter for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA, USACenter for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USAPD-1 checkpoint inhibitors have 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 show a dramatic clinical response to treatment. Despite intense biomarker discovery efforts, no single robust, prognostic correlation has emerged as a valid outcome predictor. Immune competent, pet dogs develop spontaneous tumors that share similar features to human cancers including chromosome aberrations, molecular subtypes, immune signatures, tumor heterogeneity, metastatic behavior, and chemotherapeutic response. As such, they represent a valuable parallel patient population in which to investigate predictive biomarkers of checkpoint inhibition. However, the lack of a validated, non-immunogenic, canine anti-PD-1 antibody for pre-clinical use hinders this comparative approach and prevents potential clinical benefits of PD-1 blockade being realized in the veterinary clinic. To address this, fully canine single-chain variable fragments (scFvs) that bind canine (c)PD-1 were isolated from a comprehensive canine scFv phage display library. Lead candidates were identified that bound with high affinity to cPD-1 and inhibited its interaction with canine PD-L1 (cPD-L1). The lead scFv candidate re-formatted into a fully canine IgGD reversed the inhibitory effects of cPD-1:cPD-L1 interaction on canine chimeric antigen receptor (CAR) T cell function. In vivo administration showed no toxicity and revealed favorable pharmacokinetics for a reasonable dosing schedule. These results pave the way for clinical trials with anti-cPD-1 in canine cancer patients to investigate predictive biomarkers and combination regimens to inform human clinical trials and bring a promising checkpoint inhibitor into the veterinary armamentarium.https://www.tandfonline.com/doi/10.1080/19420862.2023.2287250Caninecheckpoint inhibitormonoclonal antibodyPD-1pharmacokinetics |
| spellingShingle | Sho Yoshimoto Nicholas Chester Ailian Xiong Enrico Radaelli Hong Wang Marc Brillantes Gayathri Gulendran Patrick Glassman Don L. Siegel Nicola J. Mason Development and pharmacokinetic assessment of a fully canine anti-PD-1 monoclonal antibody for comparative translational research in dogs with spontaneous tumors mAbs Canine checkpoint inhibitor monoclonal antibody PD-1 pharmacokinetics |
| title | Development and pharmacokinetic assessment of a fully canine anti-PD-1 monoclonal antibody for comparative translational research in dogs with spontaneous tumors |
| title_full | Development and pharmacokinetic assessment of a fully canine anti-PD-1 monoclonal antibody for comparative translational research in dogs with spontaneous tumors |
| title_fullStr | Development and pharmacokinetic assessment of a fully canine anti-PD-1 monoclonal antibody for comparative translational research in dogs with spontaneous tumors |
| title_full_unstemmed | Development and pharmacokinetic assessment of a fully canine anti-PD-1 monoclonal antibody for comparative translational research in dogs with spontaneous tumors |
| title_short | Development and pharmacokinetic assessment of a fully canine anti-PD-1 monoclonal antibody for comparative translational research in dogs with spontaneous tumors |
| title_sort | development and pharmacokinetic assessment of a fully canine anti pd 1 monoclonal antibody for comparative translational research in dogs with spontaneous tumors |
| topic | Canine checkpoint inhibitor monoclonal antibody PD-1 pharmacokinetics |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2023.2287250 |
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