Humanized PD-1/PD-L1 (HuPD) mice facilitate the direct functional comparison of immune checkpoint inhibitors in vivo
| Autor: | Whitney Jo Barham, Susan M. Harrington, Xin Liu, Haidong Dong |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 202:195.1-195.1 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.202.supp.195.1 |
| Popis: | Though anti-PD-1/L1 antibody therapies have generated unprecedented responses in a limited number of patients, the biological and immunological parameters that define their effective use are still largely unknown. The absence of appropriate pre-clinical models has limited our ability to compare the mechanistic differences between the approved PD-1/L1 antibodies in vivo and to determine the context in which each might be most effective. To address this critical need, we have produced humanized PD-1 and PD-L1 mice in which the extracellular domains (antibody binding sites) of mouse PD-1 and PD-L1 are replaced with the sequences of human PD-1 and PD-L1. The PD-1 and PD-L1 in the resulting “HuPD” mice can be recognized by FDA-approved antibodies, while the intracellular domains are kept intact for normal downstream signals. Following characterization of the new mouse model, in our first in vivo treatment studies, HuPD mice were immunized with OVA/Poly I:C in the context of FDA-approved PD-1/L1 antibodies and antigen-specific T cell production was quantified. Nivolumab, Pembrolizumab, and Atezolizumab all increased effector CD8+T cell production against the OVA antigen as expected given their immune stimulating function. Surprisingly, OVA-tetramer staining was unable to detect antigen-specific CD8+T cells in the spleens of immunized mice treated with Avelumab. This may reflect the unique ability of Avelumab to induce ADCC, and indicates that our model is capable of distinguishing key differences among the antibodies in vivo. Ongoing studies will identify how these differences might be exploited to render the most effective results for patients in a variety of tumor types and immune environments. |
| Databáze: | OpenAIRE |
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