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

被引：273

作者：

Schaefer, Gabriele ^{[1
]}

Haber, Lauric ^{[2
]}

Crocker, Lisa M. ^{[3
]}

Shia, Steven ^{[4
]}

Shao, Lily ^{[1
]}

Dowbenko, Donald ^{[1
]}

Totpal, Klara ^{[3
]}

Wong, Anne ^{[5
]}

Lee, Chingwei V. ^{[2
]}

Stawicki, Scott ^{[2
]}

Clark, Robyn ^{[3
]}

Fields, Carter ^{[1
]}

Phillips, Gail D. Lewis ^{[1
]}

Prell, Rodney A. ^{[6
]}

Danilenko, Dimitry M. ^{[6
]}

Franke, Yvonne ^{[4
]}

Stephan, Jean-Philippe ^{[5
]}

Hwang, Jiyoung ^{[4
]}

Wu, Yan ^{[2
]}

Bostrom, Jenny ^{[2
]}

Sliwkowski, Mark X. ^{[1
]}

Fuh, Germaine ^{[2
]}

Eigenbrot, Charles ^{[2
,4
]}

机构：

[1] Genentech Inc, Dept Res Oncol, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Antibody Engn, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Translat Oncol, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Biol Struct, San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Assay Automat Technol, San Francisco, CA 94080 USA

[6] Genentech Inc, Dept Safety Assessment, San Francisco, CA 94080 USA

来源：

CANCER CELL | 2011年 / 20卷 / 04期

关键词：

GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; METASTATIC COLORECTAL-CANCER; TYROSINE KINASE INHIBITORS; MONOCLONAL-ANTIBODY; ACQUIRED-RESISTANCE; ACTIVATION; THERAPY; GEFITINIB; ERBB3;

D O I：

10.1016/j.ccr.2011.09.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：472 / 486

页数：15

共 51 条

[1] Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth [J].

Agus, DB ;

Akita, RW ;

Fox, WD ;

Lewis, GD ;

Higgins, B ;

Pisacane, PI ;

Lofgren, JA ;

Tindell, C ;

Evans, DP ;

Maiese, K ;

Scher, HI ;

Sliwkowski, MX .

CANCER CELL, 2002, 2 (02) :127-137

[2] Dual mode of action of a human anti-epidermal growth factor receptor monoclonal antibody for cancer therapy [J].

Bleeker, WK ;

van Bueren, JJL ;

van Ojik, HH ;

Gerritsen, AF ;

Pluyter, M ;

Houtkamp, M ;

Halk, E ;

Goldstein, J ;

Schuurman, J ;

van Dijk, MA ;

van de Winkel, JGJ ;

Parren, PWHI .

JOURNAL OF IMMUNOLOGY, 2004, 173 (07) :4699-4707

[3] Variants of the Antibody Herceptin That Interact with HER2 and VEGF at the Antigen Binding Site [J].

Bostrom, Jenny ;

Yu, Shang-Fan ;

Kan, David ;

Appleton, Brent A. ;

Lee, Chingwei V. ;

Billeci, Karen ;

Man, Wenyan ;

Peale, Franklin ;

Ross, Sarajane ;

Wiesmann, Christian ;

Fuh, Germaine .

SCIENCE, 2009, 323 (5921) :1610-1614

[4] Inactivation of Akt by the epidermal growth factor receptor inhibitor erlotinib is mediated by HER-3 in pancreatic and colorectal tumor cell lines and contributes to erlotinib sensitivity [J].

Buck, Elizabeth ;

Eyzaguirre, Alexandra ;

Haley, John D. ;

Gibson, Neil W. ;

Cagnoni, Pablo ;

Iwata, Kenneth K. .

MOLECULAR CANCER THERAPEUTICS, 2006, 5 (08) :2051-2059

[5] HER3 Comes of Age: New Insights into Its Functions and Role in Signaling, Tumor Biology, and Cancer Therapy [J].

Campbell, Marcia R. ;

Amin, Dhara ;

Moasser, Mark M. .

CLINICAL CANCER RESEARCH, 2010, 16 (05) :1373-1383

[6]

CARRAWAY KL, 1994, J BIOL CHEM, V269, P14303

[7]

Chames P, 2009, IDRUGS, V12, P276

[8] Structure of the extracellular region of HER3 reveals an interdomain tether [J].

Cho, HS ;

Leahy, DJ .

SCIENCE, 2002, 297 (5585) :1330-1333

[9] QUANTITATIVE-ANALYSIS OF DOSE-EFFECT RELATIONSHIPS - THE COMBINED EFFECTS OF MULTIPLE-DRUGS OR ENZYME-INHIBITORS [J].

CHOU, TC ;

TALALAY, P .

ADVANCES IN ENZYME REGULATION, 1984, 22 :27-55

[10] Drug therapy: EGFR antagonists in cancer treatment [J].

Ciardiello, Fortunato ;

Tortora, Giampaolo .

NEW ENGLAND JOURNAL OF MEDICINE, 2008, 358 (11) :1160-1174

← 1 2 3 4 5 6 →