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Abstract
Antibodies directed against CD22 have been used in radioimmunotherapy (RIT) clinical trials to treat patients with diffuse large B-cell lymphoma (DLBCL) with promising results. However, relevant preclinical models are needed to facilitate the evaluation and optimization of new protocols. Spontaneous DLBCL in dogs is a tumor model that may help accelerate the development of new methodologies and therapeutic strategies for RIT targeting CD22. Seven murine monoclonal antibodies specific for canine CD22 were produced by the hybridoma method and characterized. The antibodies' affinity and epitopic maps, their internalization capability and usefulness for diagnosis in immunohistochemistry were determined. Biodistribution and PET imaging on a mouse xenogeneic model of dog DLBCL was used to choose the most promising antibody for our purposes. PET-CT results confirmed biodistribution study observations and allowed tumor localization. The selected antibody, 10C6, was successfully used on a dog with spontaneous DLBCL for SPECT-CT imaging in the context of disease staging, validating its efficacy for diagnosis and the feasibility of future RIT assays. This first attempt at phenotypic imaging on dogs paves the way to implementing quantitative imaging methodologies that would be transposable to humans in a theranostic approach. Taking into account the feedback of existing human radioimmunotherapy clinical trials targeting CD22, animal trials are planned to investigate protocol improvements that are difficult to consider in humans due to ethical concerns.
Highlights
Radioimmunotherapy (RIT) using an anti-CD20 antibody radiolabeled with yttrium-90 is approved for the treatment of patients with relapsed or refractory follicular lymphoma (FL) or in consolidation after a front-line induction chemotherapy [1,2,3,4]
A soluble form of canine CD22 usable for mice immunization and for monoclonal antibody characterization was produced by stable transfection into Chinese hamster ovary (CHO) cells
Because we wanted to use this antigen for nuclear medicine applications, we chose to perform hybridoma supernatant screening by flow cytometry analysis in order to discard any antibodies that would recognize epitopes on the unfold antigen in ELISA test
Summary
Radioimmunotherapy (RIT) using an anti-CD20 antibody radiolabeled with yttrium-90 (ibritumomab tiuxetan/Zevalin R ) is approved for the treatment of patients with relapsed or refractory follicular lymphoma (FL) or in consolidation after a front-line induction chemotherapy [1,2,3,4]. Performing RIT protocols in first-line treatment is not currently feasible until further clinical data is obtained regarding safety and efficacy in later-line treatment. For these reasons, relevant preclinical models are needed to facilitate the evaluation and optimization of new protocols. The relevance of rodent models of lymphoma is limited to the small number of lymphoma cell lines that are able to grow in vivo. These few cell lines do not represent the large physiopathological diversity of human tumor subtypes and the inter-individual heterogeneity of patients [15, 16]
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