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...

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Main Authors: Nicola J. Mason (Author), Nicholas Chester (Author), Ailian Xiong (Author), Antonia Rotolo (Author), Ying Wu (Author), Sho Yoshimoto (Author), Patrick Glassman (Author), Gayathri Gulendran (Author), Don L. Siegel (Author)
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Published: Taylor & Francis Group, 2021-01-01T00:00:00Z.
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001 doaj_3d1a06698fe447c889e66b51ed9b5518
042 |a dc 
100 1 0 |a Nicola J. Mason  |e author 
700 1 0 |a Nicholas Chester  |e author 
700 1 0 |a Ailian Xiong  |e author 
700 1 0 |a Antonia Rotolo  |e author 
700 1 0 |a Ying Wu  |e author 
700 1 0 |a Sho Yoshimoto  |e author 
700 1 0 |a Patrick Glassman  |e author 
700 1 0 |a Gayathri Gulendran  |e author 
700 1 0 |a Don L. Siegel  |e author 
245 0 0 |a Development of a fully canine anti-canine CTLA4 monoclonal antibody for comparative translational research in dogs with spontaneous tumors 
260 |b Taylor & Francis Group,   |c 2021-01-01T00:00:00Z. 
500 |a 10.1080/19420862.2021.2004638 
500 |a 1942-0870 
500 |a 1942-0862 
520 |a 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. 
546 |a EN 
690 |a Checkpoint inhibitor 
690 |a canine 
690 |a CTLA4 
690 |a large animal model 
690 |a monoclonal antibody 
690 |a single chain variable fragment 
690 |a Therapeutics. Pharmacology 
690 |a RM1-950 
690 |a Immunologic diseases. Allergy 
690 |a RC581-607 
655 7 |a article  |2 local 
786 0 |n mAbs, Vol 13, Iss 1 (2021) 
787 0 |n https://www.tandfonline.com/doi/10.1080/19420862.2021.2004638 
787 0 |n https://doaj.org/toc/1942-0862 
787 0 |n https://doaj.org/toc/1942-0870 
856 4 1 |u https://doaj.org/article/3d1a06698fe447c889e66b51ed9b5518  |z Connect to this object online.