Unbiased Combinatorial Screening Identifies a Bispecific IgG1 that Potently Inhibits HER3 Signaling via HER2-Guided Ligand Blockade

Adams, 2010, PHENIX: a comprehensive Python-based system for macromolecular structure solution, Acta Crystallogr. D Biol. Crystallogr., 66, 213, 10.1107/S0907444909052925 Battye, 2011, iMOSFLM: a new graphical interface for diffraction-image processing with MOSFLM, Acta Crystallogr. D Biol. Crystallogr., 67, 271, 10.1107/S0907444910048675 Berlin, 2011, A first-in-human phase I study of U3-1287 (AMG 888), a HER3 inhibitor, in patients (pts) with advanced solid tumors, J. Clin. Oncol., 29, 3026, 10.1200/jco.2011.29.15_suppl.3026 Bria, 2008, Trastuzumab cardiotoxicity: biological hypotheses and clinical open issues, Expert Opin. Biol. Ther., 8, 1963, 10.1517/14728220802517935 Capparelli, 2015, Fibroblast-derived neuregulin 1 promotes compensatory ErbB3 receptor signaling in mutant BRAF melanoma, J. Biol. Chem., 290, 24267, 10.1074/jbc.M115.657270 Chakrabarty, 2012, Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors, Proc. Natl. Acad. Sci. USA, 109, 2718, 10.1073/pnas.1018001108 Chandarlapaty, 2011, AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity, Cancer Cell, 19, 58, 10.1016/j.ccr.2010.10.031 de Kruif, 1995, Selection and application of human single chain Fv antibody fragments from a semi-synthetic phage antibody display library with designed CDR3 regions, J. Mol. Biol., 248, 97, 10.1006/jmbi.1995.0204 de Kruif, 2009, Human immunoglobulin repertoires against tetanus toxoid contain a large and diverse fraction of high-affinity promiscuous V(H) genes, J. Mol. Biol., 387, 548, 10.1016/j.jmb.2009.02.009 De Nardis, 2017, A new approach for generating bispecific antibodies based on a common light chain format and the stable architecture of human immunoglobulin G1, J. Biol. Chem., 292, 14706, 10.1074/jbc.M117.793497 Emsley, 2010, Features and development of Coot, Acta Crystallogr. D Biol. Crystallogr., 66, 486, 10.1107/S0907444910007493 Evans, 2013, How good are my data and what is the resolution?, Acta Crystallogr. D Biol. Crystallogr., 69, 1204, 10.1107/S0907444913000061 Fernandez-Cuesta, 2014, CD74-NRG1 fusions in lung adenocarcinoma, Cancer Discov., 4, 415, 10.1158/2159-8290.CD-13-0633 Franke, 2009, DAMMIF, a program for rapid ab-initio shape determination in small-angle scattering, J. Appl. Crystallogr., 42, 342, 10.1107/S0021889809000338 Garner, 2013, An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin, Cancer Res., 73, 6024, 10.1158/0008-5472.CAN-13-1198 Garrett, 2013, Dual blockade of HER2 in HER2-overexpressing tumor cells does not completely eliminate HER3 function, Clin. Cancer Res., 19, 610, 10.1158/1078-0432.CCR-12-2024 Gassmann, 1995, Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor, Nature, 378, 390, 10.1038/378390a0 Gijsen, 2010, HER2 phosphorylation is maintained by a PKB negative feedback loop in response to anti-HER2 herceptin in breast cancer, PLoS Biol., 8, e1000563, 10.1371/journal.pbio.1000563 Hegde, 2013, Blocking NRG1 and other ligand-mediated Her4 signaling enhances the magnitude and duration of the chemotherapeutic response of non-small cell lung cancer, Sci. Transl. Med., 5, 171ra118, 10.1126/scitranslmed.3004438 Holbro, 2003, The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation, Proc. Natl. Acad. Sci. USA, 100, 8933, 10.1073/pnas.1537685100 Junttila, 2009, Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941, Cancer Cell, 15, 429, 10.1016/j.ccr.2009.03.020 Kodack, 2017, The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation, Sci. Transl. Med., 9, eaal4682, 10.1126/scitranslmed.aal4682 Konarev, 2003, Manipulations with experimental 1D small-angle scattering data, J. Appl. Crystallogr., 36, 1277, 10.1107/S0021889803012779 Koninki, 2010, Multiple molecular mechanisms underlying trastuzumab and lapatinib resistance in JIMT-1 breast cancer cells, Cancer Lett., 294, 211, 10.1016/j.canlet.2010.02.002 Kontermann, 2015, Bispecific antibodies, Drug Discov. Today, 20, 838, 10.1016/j.drudis.2015.02.008 Landgraf, 2000, Heregulin reverses the oligomerization of HER3, Biochemistry, 39, 8503, 10.1021/bi000953+ Lee-Hoeflich, 2008, A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy, Cancer Res., 68, 5878, 10.1158/0008-5472.CAN-08-0380 Lee, 2015, Inhibition of ErbB3 by a monoclonal antibody that locks the extracellular domain in an inactive configuration, Proc. Natl. Acad. Sci. USA, 112, 13225, 10.1073/pnas.1518361112 Lewis Phillips, 2013, Dual targeting of HER2-positive cancer with trastuzumab-emtansine (T-DM1) and pertuzumab: critical role for neuregulin blockade in anti-tumor response to combination therapy, Clin. Cancer Res., 15, 456 Liu, 2016, Randomized phase II trial of seribantumab in combination with paclitaxel in patients with advanced platinum-resistant or -refractory ovarian cancer, J. Clin. Oncol., 34, 4345, 10.1200/JCO.2016.67.1891 Liu, 2012, A single ligand is sufficient to activate EGFR dimers, Proc. Natl. Acad. Sci. USA, 109, 10861, 10.1073/pnas.1201114109 McCoy, 2007, Phaser crystallographic software, J. Appl. Crystallogr., 40, 658, 10.1107/S0021889807021206 McDonagh, 2012, Antitumor activity of a novel bispecific antibody that targets the ErbB2/ErbB3 oncogenic unit and inhibits heregulin-induced activation of ErbB3, Mol. Cancer Ther., 11, 582, 10.1158/1535-7163.MCT-11-0820 Mirschberger, 2013, RG7116, a therapeutic antibody that binds the inactive HER3 receptor and is optimized for immune effector activation, Cancer Res., 73, 5183, 10.1158/0008-5472.CAN-13-0099 Mori, 2007, Non-fucosylated therapeutic antibodies: the next generation of therapeutic antibodies, Cytotechnology, 55, 109, 10.1007/s10616-007-9103-2 Morrison, 2013, ErbB3 downregulation enhances luminal breast tumor response to antiestrogens, J. Clin. Invest., 123, 4329, 10.1172/JCI66764 Mukai, 2016, Patritumab plus trastuzumab and paclitaxel in human epidermal growth factor receptor 2-overexpressing metastatic breast cancer, Cancer Sci., 107, 1465, 10.1111/cas.13017 Mukherjee, 2011, Profiling the HER3/PI3K pathway in breast tumors using proximity-directed assays identifies correlations between protein complexes and phosphoproteins, PLoS One, 6, e16443, 10.1371/journal.pone.0016443 Muller-Tidow, 2005, Identification of metastasis-associated receptor tyrosine kinases in non-small cell lung cancer, Cancer Res., 65, 1778, 10.1158/0008-5472.CAN-04-3388 Musolino, 2008, Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer, J. Clin. Oncol., 26, 1789, 10.1200/JCO.2007.14.8957 Narayan, 2009, Trastuzumab-induced HER reprogramming in "resistant" breast carcinoma cells, Cancer Res., 69, 2191, 10.1158/0008-5472.CAN-08-1056 Nonagase, 2016, Heregulin-expressing HER2-positive breast and gastric cancer exhibited heterogeneous susceptibility to the anti-HER2 agents lapatinib, trastuzumab and T-DM1, Oncotarget, 7, 84860, 10.18632/oncotarget.12743 Ocana, 2013, HER3 overexpression and survival in solid tumors: a meta-analysis, J. Natl. Cancer Inst., 105, 266, 10.1093/jnci/djs501 Paterson, 2014, PET imaging of tumours with a 64Cu labeled macrobicyclic cage amine ligand tethered to Tyr3-octreotate, Dalton Trans., 43, 1386, 10.1039/C3DT52647J Paz-Arez, 2017, P3.02b-045 patritumab plus erlotinib in EGFR wild-type advanced non-small cell lung cancer (NSCLC): part a results of HER3-lung study, J. Thorac. Oncol., 12, S1214, 10.1016/j.jtho.2016.11.1712 Pradeep, 2014, Hematogenous metastasis of ovarian cancer: rethinking mode of spread, Cancer Cell, 26, 77, 10.1016/j.ccr.2014.05.002 Reynolds, 2014, A phase 1 study of LJM716 in patients with esophageal squamous cell carcinoma, head and neck cancer, or HER2-overexpressing metastatic breast or gastric cancer, J. Clin. Oncol., 32, 2517, 10.1200/jco.2014.32.15_suppl.2517 Retter, 2005, VBASE2, an integrative V gene database, Nucleic Acids Res., 33, 671, 10.1093/nar/gki088 Ritter, 2007, Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network, Clin. Cancer Res., 13, 4909, 10.1158/1078-0432.CCR-07-0701 Saunus, 2015, Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance, J. Pathol., 237, 363, 10.1002/path.4583 Schaefer, 2011, A two-in-one antibody against HER3 and EGFR has superior inhibitory activity compared with monospecific antibodies, Cancer Cell, 20, 472, 10.1016/j.ccr.2011.09.003 Schoeberl, 2010, An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation, Cancer Res., 70, 2485, 10.1158/0008-5472.CAN-09-3145 Schoeberl, 2009, Therapeutically targeting ErbB3: a key node in ligand-induced activation of the ErbB receptor-PI3K axis, Sci. Signal., 2, ra31, 10.1126/scisignal.2000352 Sequist, 2014, A randomized phase 2 trial of MM-121, a fully human monoclonal antibody targeting ErbB3, in combination with erlotinib in EGFR wild-type NSCLC patients, J. Clin. Oncol., 32, 8051, 10.1200/jco.2014.32.15_suppl.8051 Sergina, 2007, Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3, Nature, 445, 437, 10.1038/nature05474 Shames, 2013, High heregulin expression is associated with activated HER3 and may define an actionable biomarker in patients with squamous cell carcinomas of the head and neck, PLoS One, 8, e56765, 10.1371/journal.pone.0056765 Sheng, 2010, An activated ErbB3/NRG1 autocrine loop supports in vivo proliferation in ovarian cancer cells, Cancer Cell, 17, 298, 10.1016/j.ccr.2009.12.047 Sliwkowski, 1994, Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin, J. Biol. Chem., 269, 14661, 10.1016/S0021-9258(17)36676-0 Svergun, 1992, Determination of the regularization parameter in indirect-transform methods using perceptual criteria, J. Appl. Crystallogr., 25, 495, 10.1107/S0021889892001663 Wilson, 2012, Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors, Nature, 487, 505, 10.1038/nature11249 Wilson, 2011, Neuregulin-1-mediated autocrine signaling underlies sensitivity to HER2 kinase inhibitors in a subset of human cancers, Cancer Cell, 20, 158, 10.1016/j.ccr.2011.07.011 Yarden, 2012, The ERBB network: at last, cancer therapy meets systems biology, Nat. Rev. Cancer, 12, 553, 10.1038/nrc3309 Yonesaka, 2017, Circulating heregulin level is associated with the efficacy of patritumab combined with erlotinib in patients with non-small cell lung cancer, Lung Cancer, 105, 1, 10.1016/j.lungcan.2016.12.018 Zhou, 2011, Structural insights into the down-regulation of overexpressed p185her2/neu protein of transformed cells by the antibody chA21, J. Biol. Chem., 286, 31676, 10.1074/jbc.M111.235184