A Two-in-One Antibody against HER3 and EGFR Has Superior Inhibitory Activity Compared with Monospecific Antibodies

Gabriele Schaefer, Lauric J. Haber, Lisa M. Crocker, Steven Shia, Lily Shao, Donald Dowbenko, Klára Tótpál, Anne Wong, Chingwei Vivian Lee, Scott Stawicki, Robyn Clark, Carter Fields, Gail D. Lewis Phillips, Rodney A. Prell, Dimitry M. Danilenko, Yvonne Franke, Jean-Philippe Stephan, Jiyoung Hwang, Yan Wu, Jenny BostromMark X. Sliwkowski, Germaine Fuh, Charles Eigenbrot

Research output: Contribution to journalArticlepeer-review

250 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)472-486
Number of pages15
JournalCANCER CELL
Volume20
Issue number4
DOIs
Publication statusPublished - 18 Oct 2011
Externally publishedYes

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