A two-in-one antibody against HER3 and EGFR has superior inhibitory activity compared with monospecific antibodies.
(2011) Cancer Cell 20: 472-486
Authors: Schaefer, G., Haber, L., Crocker, L.M., Shia, S., Shao, L., Dowbenko, D., Totpal, K., Wong, A., Lee, C.V., Stawicki, S., Clark, R., Fields, C., Lewis Phillips, G.D., Prell, R.A., Danilenko, D.M., Franke, Y., Stephan, J.P., Hwang, J., Wu, Y., Bostrom, J., Sliwkowski, M.X., Fuh, G., Eigenbrot, C.
Abstract
Extensive crosstalk among ErbB/HER receptors suggests that blocking signaling from more than one family member may be essential to effectively treat cancer and limit drug resistance. We generated a conventional IgG molecule MEHD7945A with dual HER3/EGFR specificity by phage display engineering and used structural and mutational studies to understand how a single antigen recognition surface binds two epitopes with high affinity. As a human IgG1, MEHD7945A exhibited dual action by inhibiting EGFR- and HER3-mediated signaling in vitro and in vivo and the ability to engage immune effector functions. Compared with monospecific anti-HER antibodies, MEHD7945A was more broadly efficacious in multiple tumor models, showing that combined inhibition of EGFR and HER3 with a single antibody is beneficial.
COA
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