Abstract 2508: GE-huMab-HER3, a novel humanized, glycoengineered HER3 antibody with enhanced ADCC and superior preclinical in vitro and in vivo efficacy

Abstract

HER3 is a member of the Human Epidermal Growth Factor Receptor (HER) family. HER3 is a kinase dead receptor, but by forming heterodimers with other HER family receptors, HER3 works as amplifier for PI3 kinase driven tumorigenesis. It has been reported that tumors treated with EGFR-, HER2- or cMET-targeted therapies can escape via HER3 activation or upregulation. HER3 is expressed in a large variety of tumors for example in non-small cell lung cancer (NSCLC), head and neck, colorectal, gastric, pancreatic, breast, ovarian and prostate cancer. Anti-HER3 antibodies can work via various mechanisms including: (1) blocking ligand (HRGs) binding to the receptor, (2) blocking heterodimerization with other HER family members (HER1, 2 and 4), (3) downregulation of the receptor from the cell surface, and (4) engaging immune effector functions such as antibody-dependent cellular cytotoxicity (ADCC). The first three mechanisms lead to inhibition of HER3 phosphorylation and downstream signaling thereby resulting in tumor cell growth inhibition, while ADCC is a mechanism of direct target cell killing triggered by cross-linking of Fc receptors on immune effector cells (e.g. NK cells, macrophages). GE-huMab-HER3 is a novel humanized and glycoengineered IgG1 antibody that binds to HER3 with high affinity. This antibody prevents ligand binding and receptor heterodimerization thereby blocking receptor phosphorylation. In various tumor xenograft models treatment with this antibody leads to substantial tumor growth inhibition. E.g. GE-huMab-HER3 treatment achieved >50% tumor growth inhibition in 10 out of 17 NSCLC models and in some cases even resulted in complete tumor remission. However, these xenograft experiments only reveal part of this antibody's therapeutic potential. A unique feature of GE-huMab-HER3 that differentiates it from other anti-HER3 antibodies, including AMG 888 and MM-121, is its ability to bind to human FcgRIIIa on immune effector cells with a 50-fold higher affinity than standard IgG1 antibodies, a property conferred by the engineered glycosylation of the antibody Fc region. Consequently, GE-huMab-HER3 exhibits superior potency and efficacy in ADCC, as shown in vitro using recombinant A549 cells and in vivo by its Fc mediated greater anti-tumor effect in A549 orthotopic mouse models compared to a non-glyco-engineered variant of the antibody, WT-huMab-HER3. The combination of strong signaling inhibition and enhanced ADCC capability renders GE-huMabHER3 a highly potent HER3-targeting agent. Phase I clinical testing of this promising novel compound is ongoing. 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 Suppl):Abstract nr 2508. doi:1538-7445.AM2012-2508

Molecular characterization of novel trispecific ErbB-cMet-IGF1R antibodies and their antigen-binding properties

“…Human growth factor (HGF), heregulin, epidermal growth factor (EGF) and insulin-like growth factor (IGF) were purchased. Antibody sequences were derived from available patents ( Kuenkele et al , 2005 ; Dennis et al , 2007 ; Bossenmaier et al , 2011 ; Umana and Mossner, 2011 ).…”

A comprehensive review of heregulins, HER3, and HER4 as potential therapeutic targets in cancer

“…[ 140 ] GE-huMab-HER3 is a glycoengineered anti-HER3 antibody that enhances antibody-dependent cell-mediated cytotoxicity and increases antitumor effect compared to the non-glycoengineered variant of the antibody WT-huMab-HER3. [ 141 ] GSK2849330 is a glycoengineered anti-HER3 monoclonal antibody that increases both complement-mediated and antibody-dependent cell-mediated cytotoxicity (CDC). [ 142 ] Phase I studies of GSK2849330 are ongoing (NCT01966445, NCT02345174) (Table 4 ).…”

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

“…Antibodies competing with NRG and avoiding ligand-induced phosphorylation of HER3 have also been reported. 137,156 (4) Tyrosine kinase inhibitors (TKIs) have been widely used to inactivate the tyrosine kinase activity of HER3s partners, and several panHER TKIs (targeting all EGFR family members) have been developed, leading to inactive heterodimers. 94 (5) HDAC inhibitors (such as entinostat) can inhibit HER3 at the transcriptional level by inducing several miRNAs, such as miR125a, miR125b and miR205.…”

“…RG7116, also called RO5479599 (GE-huMab-HER3), 137 is a humanized glycoengineered IgG1 directed to domain I of HER3. This antibody prevents ligand binding and receptor heterodimerization, thereby blocks receptor phosphorylation and prevents downstream activation ok AKT.…”