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Development of a fully canine anti-canine CTLA4 monoclonal antibody for comparative translational research in dogs with spontaneous tumors.

ABSTRACT: 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.

SUBMITTER: Mason NJ

PROVIDER: S-EPMC8726733 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundLarge animal models, such as the dog, are increasingly being used for studying diseases including gastrointestinal (GI) disorders. Dogs share similar environmental, genomic, anatomical, and intestinal physiologic features with humans. To bridge the gap between commonly used animal models, such as rodents, and humans, and expand the translational potential of the dog model, we developed a three-dimensional (3D) canine GI organoid (enteroid and colonoid) system. Organoids have recently gained interest in translational research as this model system better recapitulates the physiological and molecular features of the tissue environment in comparison with two-dimensional cultures.ResultsOrganoids were derived from tissue of more than 40 healthy dogs and dogs with GI conditions, including inflammatory bowel disease (IBD) and intestinal carcinomas. Adult intestinal stem cells (ISC) were isolated from whole jejunal tissue as well as endoscopically obtained duodenal, ileal, and colonic biopsy samples using an optimized culture protocol. Intestinal organoids were comprehensively characterized using histology, immunohistochemistry, RNA in situ hybridization, and transmission electron microscopy, to determine the extent to which they recapitulated the in vivo tissue characteristics. Physiological relevance of the enteroid system was defined using functional assays such as optical metabolic imaging (OMI), the cystic fibrosis transmembrane conductance regulator (CFTR) function assay, and Exosome-Like Vesicles (EV) uptake assay, as a basis for wider applications of this technology in basic, preclinical and translational GI research. We have furthermore created a collection of cryopreserved organoids to facilitate future research.ConclusionsWe establish the canine GI organoid systems as a model to study naturally occurring intestinal diseases in dogs and humans, and that can be used for toxicology studies, for analysis of host-pathogen interactions, and for other translational applications.

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Development of a fully canine anti-canine CTLA4 monoclonal antibody for comparative translational research in dogs with spontaneous tumors.

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