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

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• 作者：Gabriele Schaefer¹ ;   ; ⁷ ; Lauric Haber² ;   ; ⁷ ; Lisa  ; M. Crocker³ ; Steven Shia⁴ ; Lily Shao¹ ; Donald Dowbenko¹ ; Klara Totpal³ ; Anne Wong⁵ ; Chingwei  ; V. Lee² ; Scott Stawicki² ; Robyn Clark³ ; Carter Fields¹ ; Gail  ; D. Lewis Phillips¹ ; Rodney  ; A. Prell⁶ ; Dimitry  ; M. Danilenko⁶ ; Yvonne Franke⁴ ; Jean-Philippe Stephan⁵ ; Jiyoung Hwang⁴ ; Yan Wu² ; Jenny Bostrom² ; Mark  ; X. Sliwkowski¹ ;   ; ^{marks@gene.com} ; Germaine Fuh² ;   ; ^{fuh.germaine@gene.com} ; Charles Eigenbrot² ;   ; ⁴ ;   ; ^{eigenbrot.c@gene.com}
• 刊名：Cancer Cell
• 出版年：2011
• 出版时间：18 October 2011
• 年：2011
• 卷：20
• 期：4
• 页码：472-486
• 全文大小：1566 K

文摘

Summary

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.