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Entire CD3ε, δ, and γ humanized mouse to evaluate human CD3-mediated therapeutics
Otoya Ueda1, Naoko A Wada1, Yasuko Kinoshita2
1Chugai Pharmaceutical Co., Ltd., Research Division, Fuji Gotemba Research Labs., 1-135, Komakado, Gotemba, Shizuoka, Japan.
Abstract:
T cell-mediated immunotherapy is an attractive strategy for treatment in various disease areas. In this therapeutic approach, the CD3 complex is one of the key molecules to modulate T cell functions; however, in many cases, we cannot evaluate the drug candidates in animal experiments because the therapeutics, usually monoclonal antibodies specific to human CD3, cannot react to mouse endogenous Cd3. Although immunodeficient mice transfused with human hematopoietic stem or precursor cells, known as humanized mice, are available for these studies, mice humanized in this manner are not completely immune competent. In this study we have succeeded in establishing a novel mouse strain in which all the three components of the Cd3 complex - Cd3ε, Cd3δ, and Cd3γ - are replaced by their human counterparts, CD3E, CD3D, and CD3G. Basic immunological assessments have confirmed that this strain of human CD3 EDG-replaced mice are entirely immune competent, and we have also demonstrated that a bispecific antibody that simultaneously binds to human CD3 and a tumor-associated antigen (e.g. ERBB2 or GPC3) can be evaluated in human CD3 EDG-replaced mice engrafted with tumors. Our mouse model provides a novel means to evaluate the in vivo efficacy of human CD3-mediated therapy.
Insights
Researchers developed a novel mouse model by replacing mouse Cd3 components with human CD3E, CD3D, and CD3G. This allows for effective evaluation of human CD3-mediated immunotherapies in immune-competent animals.
Area of Science:
- Immunology
- Biotechnology
Background:
- T cell-mediated immunotherapy is a promising treatment strategy.
- Evaluating human CD3-targeting therapeutics in animal models is challenging due to species-specific CD3 complex differences.
- Existing humanized mouse models lack full immune competence.
Purpose of the Study:
- To establish a novel mouse strain that fully expresses human CD3 components for immunotherapy research.
- To enable in vivo evaluation of human CD3-mediated therapies and bispecific antibodies.
Main Methods:
- Generation of a novel mouse strain by replacing endogenous mouse Cd3ε, Cd3δ, and Cd3γ genes with their human counterparts (CD3E, CD3D, CD3G).
- Comprehensive immunological assessments to confirm immune competence.
- In vivo evaluation of bispecific antibodies targeting human CD3 and tumor antigens in engrafted mice.
Main Results:
- Successfully established a mouse strain with human CD3E, CD3D, and CD3G components.
- Confirmed that the human CD3 EDG-replaced mice are fully immune competent.
- Demonstrated the utility of this model for evaluating bispecific antibodies against tumor-associated antigens.
Conclusions:
- The novel human CD3 EDG-replaced mouse model offers a robust platform for preclinical assessment of human CD3-mediated immunotherapies.
- This model overcomes limitations of previous models, enabling more accurate in vivo efficacy studies.