An Antibody That Locks HER3 in the Inactive Conformation Inhibits Tumor Growth Driven by HER2 or Neuregulin

Abstract

HER2/HER3 dimerization resulting from overexpression of HER2 or neuregulin (NRG1) in cancer leads to HER3-mediated oncogenic activation of PI3K signaling. Although ligand-blocking HER3 antibodies inhibit NRG1-driven tumor growth, they are ineffective against HER2-drive 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 and was similarly active 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.

Fibroblast-derived Neuregulin 1 Promotes Compensatory ErbB3 Receptor Signaling in Mutant BRAF Melanoma

“…Our findings also have relevance to other tumor types in which ErbB3 has been implicated in driving resistance to targeted inhibitors (19,20). ErbB2-targeting antibodies are already Food and Drug Administration-approved for breast cancer, and there is considerable research activity with ErbB3-neutralizing antibodies for several cancer types (47,48).…”

Inhibition of ErbB3 by a monoclonal antibody that locks the extracellular domain in an inactive configuration

“…Similarly, treatments with other antibodies against ErbB3 or anti-ErbB2 (such as trastuzumab or pertuzumab) also yield incomplete inhibition of signaling (20,21). ErbB2-mediated signaling in this context could result from the formation of several homo-and heterodimer species nucleated by ErbB2, and therefore treatment with a single antibody alone is insufficient to inhibit signaling fully.…”

“…Therefore, KTN3379 allosterically blocks NRG binding to ErbB3 by preventing domains 1 and 3 from simultaneously binding the ligand, revealing a mechanism of action that is distinct from that of other ErbB antagonists. SI Discussion contains a brief discussion of a previously published antibody (20) that blocks ErbB3 activation through an alternate allosteric mechanism.…”

Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

“…Importantly, this mAb does not inhibit NRG binding, and it acts synergistically with anti-EGFR (cetuximab) and anti-HER2 (trastuzumab) antibodies. 122 The result of a phase 1 clinical trial testing the safety LJM716 in combination with trastuzumab in HER2 positive patients (breast and gastric cancer), show mild to moderate adverse effects and some encouraging case of partial response (6%) and stable disease (36%). 123 In combination with BYL719 (a PI3K inhibitor), either alone or with trastuzumab, LJM716 showed promising results on HER2-positive breast cancer cells.…”