Author/Authors :
Schaefer، نويسنده , , Gabriele and Haber، نويسنده , , Lauric and Crocker، نويسنده , , Lisa M. and Shia، نويسنده , , Steven and Shao، نويسنده , , Lily and Dowbenko، نويسنده , , Donald and Totpal، نويسنده , , Klara and Wong، نويسنده , , Anne and Lee، نويسنده , , Chingwei V. and Stawicki، نويسنده , , Scott and Clark، نويسنده , , Robyn and Fields، نويسنده , , Carter and Lewis Phillips، نويسنده , , Gail D. and Prell، نويسنده , , Rodney A. and Danilenko، نويسنده , , Dimitry M. and Franke، نويسنده , , Yvonne and Stephan، نويسنده , , Jean-Philippe and Hwang، نويسنده , , Jiyoung and Wu، نويسنده , , Yan and Bostrom، نويسنده , , Jenny and Sliwkowski، نويسنده , , Mark X. and Fuh، نويسنده , , Germaine and Eigenbrot، نويسنده , , Charles، نويسنده ,
Abstract :
Summary
ive 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.
