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Published on: September 27, 2021
A humanized CD3ε-knock-in mouse model for pre-clinical testing of anti-human CD3 therapy
Joel Crespo1, Yi Ting Koh1, Ningjie Hu1
1Immunology Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United States of America.
Abstract:
Pre-clinical murine models are critical for translating drug candidates from the bench to the bedside. There is interest in better understanding how anti-human CD3 therapy works based on recent longitudinal studies of short-term administration. Although several models have been created in this pursuit, each have their own advantages and disadvantages in Type-1 diabetes. In this study, we report a murine genetic knock-in model which expresses both a murine and a humanized-CD3ε-exon, rendering it sensitive to manipulation with anti-human CD3. These huCD3εHET mice are viable and display no gross abnormalities. Specifically, thymocyte development and T cell peripheral homeostasis is unaffected. We tested immune functionality of these mice by immunizing them with T cell-dependent antigens and no differences in antibody titers compared to wild type mice were recorded. Finally, we performed a graft-vs-host disease model that is driven by effector T cell responses and observed a wasting disease upon transfer of huCD3εHET T cells. Our results show a viable humanized CD3 murine model that develops normally, is functionally engaged by anti-human CD3 and can instruct on pre-clinical tests of anti-human CD3 antibodies.
Insights
A new humanized CD3 epsilon (huCD3ε) knock-in mouse model is viable and develops normally. This model is sensitive to anti-human CD3 therapy, proving useful for pre-clinical drug testing in Type-1 diabetes research.
Area of Science:
- Immunology
- Pre-clinical drug development
- Transgenic animal models
Background:
- Pre-clinical murine models are essential for drug development.
- Understanding anti-human CD3 therapy requires suitable models.
- Existing models for Type-1 diabetes have limitations.
Purpose of the Study:
- To develop and characterize a novel murine model for anti-human CD3 therapy research.
- To assess the viability and normal development of the humanized CD3 epsilon (huCD3ε) knock-in mice.
- To evaluate the utility of this model in pre-clinical testing of anti-human CD3 antibodies.
Main Methods:
- Generation of a genetic knock-in mouse model expressing a humanized CD3ε exon.
- Assessment of mouse viability, gross abnormalities, thymocyte development, and peripheral T cell homeostasis.
- Immunization with T cell-dependent antigens to test immune functionality.
- Graft-versus-host disease model to evaluate effector T cell responses.
Main Results:
- The huCD3εHET mice are viable with no gross abnormalities.
- Thymocyte development and peripheral T cell homeostasis are unaffected.
- Immune functionality is comparable to wild-type mice, with similar antibody titers.
- The model exhibits a wasting disease in a graft-versus-host disease model upon T cell transfer.
Conclusions:
- A viable humanized CD3ε murine model was successfully created.
- The model develops normally and is functionally responsive to anti-human CD3 therapy.
- This model is suitable for pre-clinical evaluation of anti-human CD3 antibodies in conditions like Type-1 diabetes.
