Using an immunocompetent mouse model expressing a humanized CD3ε chain and bispecific T cell engager (BiTE) molecules directed against mouse CD19, mouse CLDN18.2, or human EPCAM antigens, researchers investigated the pharmacokinetic and pharmacodynamic parameters and immune correlates associated with BiTE efficacy across multiple syngeneic solid-tumor models.
[Science Translational Medicine]
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Belmontes, B., Sawant, D. V., Zhong, W., Tan, H., Kaul, A., Aeffner, F., O’Brien, S. A., Chun, M., Noubade, R., Eng, J., Ma, H., Muenz, M., Li, P., Alba, B. M., Thomas, M., Cook, K., Wang, X., DeVoss, J., Egen, J. G., & Nolan-Stevaux, O. (2021). Immunotherapy combinations overcome resistance to bispecific T cell engager treatment in T cell–cold solid tumors. Science Translational Medicine, 13(608). https://doi.org/10.1126/scitranslmed.abd1524 Cite