B6-hCD3/hEPCAM Mice

Catalog Number: C001694

Strain Name: C57BL/6N;6JCya-Cd3tm2(hCD3)Epcamtm1(hEPCAM)/Cya

Genetic Background: C57BL/6N;6JCya

Reproduction: Homozygous B6-hCD3 mice x Homozygous B6-EPCAM mice

 

Strain Description

Cluster of Differentiation 3 (CD3) is a protein complex that acts as a co-receptor for T cells and is involved in the activation of cytotoxic T cells (CTLs) and helper T cells (THs). CD3 consists of five polypeptide chains: γ, δ, ε, ζ, and η, all of which are transmembrane proteins. The transmembrane regions of CD3 molecules connect with the transmembrane regions of TCR's two polypeptide chains through salt bridges, forming the TCR-CD3 complex, which is essential for T cell antigen recognition [1-2]. After TCR recognizes an antigen, the activation signal is transduced by CD3 into the T cell. CD3 is highly specific at all developmental stages of T cells, thus it is considered a T cell-specific immunohistochemical marker. Additionally, CD3 is present in almost all T cell lymphomas and leukemias and can be used to distinguish between morphologically similar B cell and bone marrow tumors. Due to its significant role in T cell activation and antigen recognition, CD3 is an important drug target in immunosuppressive therapy for type 1 diabetes and other autoimmune diseases [3].

The EPCAM gene encodes a transmembrane glycoprotein, Epithelial Cell Adhesion Molecule (EPCAM), also known as CD326 or Trop-1, which mediates calcium-independent homotypic cell adhesion and participates in fundamental processes including cell adhesion, migration, proliferation, and signal transduction, thereby maintaining epithelial tissue integrity [4]. While normally expressed on the surface of epithelial cells in organs such as the gastrointestinal tract, lungs, and skin, EPCAM is frequently overexpressed in various cancers, including colorectal, breast, and pancreatic carcinomas, but is largely absent or weakly expressed in healthy squamous epithelia [4]. Structurally, EPCAM comprises an extracellular domain (EpEX) mediating intercellular adhesion, a transmembrane domain, and a short intracellular domain (EpICD). Upon proteolytic cleavage by ADAM17 and γ-secretase, EpICD translocates to the nucleus, activating oncogenic pathways such as Wnt/β-catenin, ERK, and FAK-AKT, which promotes epithelial-mesenchymal transition (EMT), tumor progression, and metastasis [5]. Notably, EPCAM serves as a marker for circulating tumor cells (CTCs) and cancer stem cells, and its downregulation during EMT can complicate advanced cancer detection [5-6]. Furthermore, dysregulated EPCAM expression is associated with congenital tufting enteropathy (CTE), a severe intestinal epithelial dysfunction [5]. Given its involvement in tumor metastasis through interaction with HGFR (c-Met), targeting EPCAM with strategies like the neutralizing antibody EpAb2-6 in combination with HGFR inhibitors has shown promising preclinical efficacy [7].

The B6-hCD3/hEPCAM mouse is obtained by crossbreeding B6-hCD3 mice (Catalog No.: C001325) with B6-hEPCAM mice. It can be used for the development of CD3/EPCAM-targeted drugs, as well as for research in tumor immunotherapy and autoimmune disease-related drugs.

 

Strain Strategy

  • B6-hCD3 Mouse Construction Strategy: The mouse Cd3e, Cd3d, and Cd3g genes which encode the three components of the CD3 complex, Cd3ε, Cd3δ, and Cd3γ, were replaced by the corresponding human homologous genes.



  • B6-hEPCAM Mouse Construction Strategy: The mouse Epcam extracellular domain (aa.33~261) will be replaced with the human EPCAM extracellular domain (aa.33~260).

Application

  • Development and Evaluation of CD3/EPCAM-Targeted Drugs;
  • Tumor Immunotherapy Research;
  • Immunosuppressive Therapy Research for Autoimmune Diseases.

 

References
[1]Dong D, Zheng L, Lin J, Zhang B, Zhu Y, Li N, Xie S, Wang Y, Gao N, Huang Z. Structural basis of assembly of the human T cell receptor-CD3 complex. Nature. 2019 Sep;573(7775):546-552.
[2]Dykhuizen M, Ceman J, Mitchen J, Zayas M, MacDougall A, Helgeland J, Rakasz E, Pauza CD. Importance of the CD3 marker for evaluating changes in rhesus macaque CD4/CD8 T-cell ratios. Cytometry. 2000 May 1;40(1):69-75.
[3]Bolt S, Routledge E, Lloyd I, Chatenoud L, Pope H, Gorman SD, Clark M, Waldmann H. The generation of a humanized, non-mitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties. Eur J Immunol. 1993 Feb;23(2):403-11.
[4]Fagotto F. EpCAM as Modulator of Tissue Plasticity. Cells. 2020 Sep 19;9(9):2128.
[5]Gires O, Pan M, Schinke H, Canis M, Baeuerle PA. Expression and function of epithelial cell adhesion molecule EpCAM: where are we after 40 years? Cancer Metastasis Rev. 2020 Sep;39(3):969-987.
[6]Lee CC, Yu CJ, Panda SS, et al. Epithelial cell adhesion molecule (EpCAM) regulates HGFR signaling to promote colon cancer progression and metastasis. J Transl Med. 2023 August;21:530.
[7]Perelmuter VM, Grigoryeva ES, Savelieva OE, et al. EpCAM-CD24+ circulating cells associated with poor prognosis in breast cancer patients. Sci Rep. 2024 May;14:12245.