Garner, Andrew P., Bialucha, Carl, Sprague, Elizabeth, Garrett, Joan T., Sheng, Qing, Li, Xiao, Sineshchekova, Olga, Saxena, Parmita, Sutton, Cammie R., Chen, Dongshu, Chen, Yan, Wang, Hui-Qin, Liang, Jinsheng, Das, Rita, Mosher, Rebecca, Gu, Jian, Huang, Alan, Haubst, Nicole, Zehetmeier, Carol, Haberl, Manuela, Kunz, Christian, Ellis, Winfried, Heidt, Analeah, Herlihy, Kara, Murtie, Joshua, Schuller, Alwin, Arteaga, Carlos L., Sellers, William and Ettenberg, Seth (2013) LJM716, an anti-HER3 antibody that locks HER3 in the inactive conformation and inhibits both HER2 and neuregulin driven tumor growth. Cancer Research, 73 (19). pp. 6024-35. ISSN 1538-7445

Abstract

Inappropriate HER2/HER3 dimerization as a result of HER2 or neuregulin (NRG1) over-expression in cancer results in HER3 mediated activation of PI3K signaling. Consequently, HER3 is a mediator of oncogenic transformation. Although ligand blocking HER3 antibodies inhibit growth of neuregulin driven xenograft models, they are generally ineffective in models of HER2 amplified cancer as HER2 mediated activation of HER3 occurs in a ligand-independent manner. LJM716 is a high affinity HER3-targeted antibody selected specifically for its ability to neutralize multiple modes of HER3 activation. LJM716 is a potent inhibitor of HER3/AKT phosphorylation and proliferation in a range of HER2 amplified and NRG1 expressing cell lines in vitro. LJM716 has single agent activity in both NRG1 expressing and HER2 amplified tumor xenografts. Combinations of LJM716 with HER2 or EGFR targeted agents are synergistic in a panel of cell lines in vitro and generate significant anti-tumor activity. LJM716 combination with trastuzumab enables more potent inhibition of signaling and cell proliferation than trastuzumab/pertuzumab combination and is equally active in vivo. To further elucidate the mechanism by which LJM716 inhibits multiple modes of HER3 activation we solved the crystal structure of LJM716 bound to HER3. We show that LJM716 binds to a conformational epitope contained within domains 2 and 4, trapping HER3 in the inactive conformation. Thus, LJM716 possesses a novel mechanism of action and based on preclinical data, combining LJM716 with either HER2 or EGFR-targeted agents may lead to greater and more sustained clinical efficacy in ErbB driven cancers compared to current treatments.

Item Type:	Article
Keywords:	Antibody, HER, EGFR, HER2, HER3, ERBB3, NRG, neuregulin, ligand-dependent, ligand-independent, cancer, feedback, SCCHN, PIK3CA, PI-3 kinase, resistance
Date Deposited:	13 Oct 2015 13:13
Last Modified:	04 Jul 2016 23:46
URI:	https://oak.novartis.com/id/eprint/10127