An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin

Andrew P. Garner, Carl U. Bialucha, Elizabeth R. Sprague, Joan T. Garrett, Qing Sheng, Sharon Li, Olga Sineshchekova, Parmita Saxena, Cammie R. Sutton, Dongshu Chen, Yan Chen, Huiqin Wang, Jinsheng Liang, Rita Das, Rebecca Mosher, Jian Gu, Alan Huang, Nicole Haubst, Carolin Zehetmeier, Manuela HaberlWinfried Elis, Christian Kunz, Analeah B. Heidt, Kara Herlihy, Joshua Murtie, Alwin Schuller, Carlos L. Arteaga, William R. Sellers, Seth A. Ettenberg

Research output: Contribution to journalArticle

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Abstract

HER2/HER3 dimerization resulting from overexpression of HER2 or neuregulin (NRG1) in cancer leads to HER3-mediated oncogenic activation of phosphoinositide 3-kinase (PI3K) signaling. Although ligand-blocking HER3 antibodies inhibit NRG1-driven tumor growth, they are ineffective against HER2-driven tumor growth because HER2 activates HER3 in a ligand-independent manner. In this study, we describe a novel HER3 monoclonal antibody (LJM716) that can neutralize multiple modes of HER3 activation, making it a superior candidate for clinical translation as a therapeutic candidate. LJM716 was a potent inhibitor of HER3/AKT phosphorylation and proliferation in HER2-amplified and NRG1-expressing cancer cells, and it displayed single-agent efficacy in tumor xenograft models. Combining LJM716 with agents that target HER2 or EGFR produced synergistic antitumor activity in vitro and in vivo. In particular, combining LJM716 with trastuzumab produced a more potent inhibition of signaling and cell proliferation than trastuzumab/pertuzumab combinations with similar activity in vivo. To elucidate its mechanism of action, we solved the structure of LJM716 bound to HER3, finding that LJM716 bound to an epitope, within domains 2 and 4, that traps HER3 in an inactive conformation. Taken together, our findings establish that LJM716 possesses a novel mechanism of action that, in combination with HER2- or EGFR-targeted agents, may leverage their clinical efficacy in ErbB-driven cancers.

Original languageEnglish (US)
Pages (from-to)6024-6035
Number of pages12
JournalCancer Research
Volume73
Issue number19
DOIs
StatePublished - Oct 1 2013

Fingerprint

Neuregulins
Antibodies
Growth
Neoplasms
Ligands
Blocking Antibodies
1-Phosphatidylinositol 4-Kinase
Dimerization
Heterografts
Epitopes
Monoclonal Antibodies
Phosphorylation
Cell Proliferation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Garner, A. P., Bialucha, C. U., Sprague, E. R., Garrett, J. T., Sheng, Q., Li, S., ... Ettenberg, S. A. (2013). An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin. Cancer Research, 73(19), 6024-6035. https://doi.org/10.1158/0008-5472.CAN-13-1198

An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin. / Garner, Andrew P.; Bialucha, Carl U.; Sprague, Elizabeth R.; Garrett, Joan T.; Sheng, Qing; Li, Sharon; Sineshchekova, Olga; Saxena, Parmita; Sutton, Cammie R.; Chen, Dongshu; Chen, Yan; Wang, Huiqin; Liang, Jinsheng; Das, Rita; Mosher, Rebecca; Gu, Jian; Huang, Alan; Haubst, Nicole; Zehetmeier, Carolin; Haberl, Manuela; Elis, Winfried; Kunz, Christian; Heidt, Analeah B.; Herlihy, Kara; Murtie, Joshua; Schuller, Alwin; Arteaga, Carlos L.; Sellers, William R.; Ettenberg, Seth A.

In: Cancer Research, Vol. 73, No. 19, 01.10.2013, p. 6024-6035.

Research output: Contribution to journalArticle

Garner, AP, Bialucha, CU, Sprague, ER, Garrett, JT, Sheng, Q, Li, S, Sineshchekova, O, Saxena, P, Sutton, CR, Chen, D, Chen, Y, Wang, H, Liang, J, Das, R, Mosher, R, Gu, J, Huang, A, Haubst, N, Zehetmeier, C, Haberl, M, Elis, W, Kunz, C, Heidt, AB, Herlihy, K, Murtie, J, Schuller, A, Arteaga, CL, Sellers, WR & Ettenberg, SA 2013, 'An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin', Cancer Research, vol. 73, no. 19, pp. 6024-6035. https://doi.org/10.1158/0008-5472.CAN-13-1198
Garner, Andrew P. ; Bialucha, Carl U. ; Sprague, Elizabeth R. ; Garrett, Joan T. ; Sheng, Qing ; Li, Sharon ; Sineshchekova, Olga ; Saxena, Parmita ; Sutton, Cammie R. ; Chen, Dongshu ; Chen, Yan ; Wang, Huiqin ; Liang, Jinsheng ; Das, Rita ; Mosher, Rebecca ; Gu, Jian ; Huang, Alan ; Haubst, Nicole ; Zehetmeier, Carolin ; Haberl, Manuela ; Elis, Winfried ; Kunz, Christian ; Heidt, Analeah B. ; Herlihy, Kara ; Murtie, Joshua ; Schuller, Alwin ; Arteaga, Carlos L. ; Sellers, William R. ; Ettenberg, Seth A. / An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin. In: Cancer Research. 2013 ; Vol. 73, No. 19. pp. 6024-6035.
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AU - Garner, Andrew P.

AU - Bialucha, Carl U.

AU - Sprague, Elizabeth R.

AU - Garrett, Joan T.

AU - Sheng, Qing

AU - Li, Sharon

AU - Sineshchekova, Olga

AU - Saxena, Parmita

AU - Sutton, Cammie R.

AU - Chen, Dongshu

AU - Chen, Yan

AU - Wang, Huiqin

AU - Liang, Jinsheng

AU - Das, Rita

AU - Mosher, Rebecca

AU - Gu, Jian

AU - Huang, Alan

AU - Haubst, Nicole

AU - Zehetmeier, Carolin

AU - Haberl, Manuela

AU - Elis, Winfried

AU - Kunz, Christian

AU - Heidt, Analeah B.

AU - Herlihy, Kara

AU - Murtie, Joshua

AU - Schuller, Alwin

AU - Arteaga, Carlos L.

AU - Sellers, William R.

AU - Ettenberg, Seth A.

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