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Mol Cancer Ther. 2017 Jul;16(7):1312-1323. doi: 10.1158/1535-7163.MCT-16-0886. Epub 2017 May 15.

Neuregulin 1 Allosterically Enhances the Antitumor Effects of the Noncompeting Anti-HER3 Antibody 9F7-F11 by Increasing Its Binding to HER3.

Le Clorennec C1,2,3,4, Bazin H5, Dubreuil O6, Larbouret C1,2,3,4, Ogier C1,2,3,4, Lazrek Y1,2,3,4, Garambois V1,2,3,4, Poul MA1,2,3,4, Mondon P7, Barret JM6, Mathis G5, Prost JF6, Pèlegrin A1,2,3,4, Chardès T8,2,3,4.

Author information

1
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.
2
INSERM U1194, Montpellier, France.
3
Université de Montpellier, Montpellier, France.
4
ICM, Institut régional du Cancer de Montpellier, France.
5
CisBio SA, Le Codolet, France.
6
GamaMabs Pharma SA, Centre Pierre Potier, Toulouse, France.
7
Millegen SA, Labège, France.
8
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France. thierry.chardes@inserm.fr.

Abstract

Exploratory clinical trials using therapeutic anti-HER3 antibodies strongly suggest that neuregulin (NRG1; HER3 ligand) expression at tumor sites is a predictive biomarker of anti-HER3 antibody efficacy in cancer. We hypothesized that in NRG1-expressing tumors, where the ligand is present before antibody treatment, anti-HER3 antibodies that do not compete with NRG1 for receptor binding have a higher receptor-neutralizing action than antibodies competing with the ligand for binding to HER3. Using time-resolved-fluorescence energy transfer (TR-FRET), we demonstrated that in the presence of recombinant NRG1, binding of 9F7-F11 (a nonligand-competing anti-HER3 antibody) to HER3 is increased, whereas that of ligand-competing anti-HER3 antibodies (H4B-121, U3-1287, Ab#6, Mab205.10.2, and MOR09825) is decreased. Moreover, 9F7-F11 showed higher efficacy than antibodies that compete with the ligand for binding to HER3. Specifically, 9F7-F11 inhibition of cell proliferation and of HER3/AKT/ERK1/2 phosphorylation as well as 9F7-F11-dependent cell-mediated cytotoxicity were higher in cancer cells preincubated with recombinant NRG1 compared with cells directly exposed to the anti-HER3 antibody. This translated in vivo into enhanced growth inhibition of NRG1-expressing BxPC3 pancreatic, A549 lung, and HCC-1806 breast cell tumor xenografts in mice treated with 9F7-F11 compared with H4B-121. Conversely, both antibodies had similar antitumor effect in NRG1-negative HPAC pancreatic carcinoma cells. In conclusion, the allosteric modulator 9F7-F11 shows increased anticancer effectiveness in the presence of NRG1 and thus represents a novel treatment strategy for NRG1-addicted tumors. Mol Cancer Ther; 16(7); 1312-23. ©2017 AACR.

PMID:
28507002
DOI:
10.1158/1535-7163.MCT-16-0886
[Indexed for MEDLINE]
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