Abstract 2733: LJM716: an anti-HER3 antibody that inhibits both HER2 and NRG driven tumor growth by trapping HER3 in the inactive conformation

HER3 (ErbB3) is a member of the ErbB family of receptor tyrosine kinases (RTK). Inappropriate HER2/ HER3 dimerization as a result of HER2 or neuregulin (NRG) 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 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 from a Human Combinatorial Antibody Library (HuCAL) 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 NRG expressing cell lines in vitro. LJM716 induced tumor regression in Fadu (NRG expressing, HNSCC) tumor xenografts and significant tumor growth inhibition (>80%) in a variety of xenograft models including BT474 (HER2 amplified breast). Furthermore, the combination of LJM716 with trastuzumab, cetuximab or PI3K- targeted agents was synergistic in a panel of in vitro cell lines while the in vivo combination of LJM716 with trastuzumab or erlotinib was efficacious in BT474 and L3.3 (pancreatic) tumor xenografts respectively. To further understand the mechanism by which LJM716 inhibits multiple modes of HER3 activation we solved the crystal structure of LJM716 bound to the HER3 extra-cellular domain. This data revealed that LJM716 binds to a novel conformational epitope contained within domains 2 and 4 and appears to trap HER3 in the inactive conformation. Interestingly, LJM716 does not block NRG binding to HER3 nor does it affect the binding affinity of the HER3/ NRG interaction. LJM716 therefore possesses a novel mechanism of action; it prevents the structural rearrangements required for HER3 activation induced by either HER2 or NRG. Thus LJM716 is the first HER3 antibody to display efficacy in both HER2 and ligand driven xenograft models. Based on preclinical data, combining LJM716 with either trastuzumab, cetuximab or PI3K- targeted agents may lead to greater and more sustained clinical efficacy in ErbB driven cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Sup