Novel humanized CD3ε mouse model for evaluation of bi-specific T-cell engager antibodies
CD3ε is one of the key signaling subunits of the CD3 co-receptor of the T cell receptor (TCR) complex. This TCR complex plays critical role in mediating T cell activation and cellular immune response. In recent years, bispecific antibodies that target human CD3ε and redirect T cell cytotoxicity toward tumor cells has been extensively investigated and some have shown clinical success and promise. However, due to the relatively low homology between the extracellular domain of human CD3 and mouse CD3, many antibodies that recognize human CD3 do not cross-react with mouse CD3. Hence, a murine model suitable for directly evaluating CD3-specific therapy is needed.
To expedite the in vivo interrogation of human CD3-based therapeutics, Biocytogen generated the B-hCD3ε mice where the extracellular domain of human CD3ε replaces that of the mouse counterpart. Here we present evidence that these humanized CD3ε mice demonstrated normal T cell development compared with wild type C57BL/6 mice. B-hCD3ε mice responded well to anti-PD-1-mediated tumor suppression and exhibited T cell depletion by an anti-human CD3 antibody. In addition, when stimulated with anti-CD3 antibody in vitro, T cells of B-hCD3ε mice showed comparable level of production of cytokines to that by T cells of wild type mice. Finally, in efficacy test, bispecific anti-human CD3/CD19 antibody blinatumomab dose-dependently inhibited MC38-hCD19 tumor growth in B-hCD3ε mice. Taken together, Biocytogen’s B-hCD3ε mice are validated and exhibit expected T cell profile, robust in vitro activity, and efficacious in vivo response to anti-human CD3 antibody and anti-human CD3 bispecific antibody. These humanized B-hCD3e mice present a useful model for accelerated in vivo evaluation of anti-human CD3 therapeutics.