4LEO

Crystal structure of anti-HER3 Fab RG7116 in complex with the extracellular domains of human Her3 (ERBB3)

Summary for 4LEO

• Entry DOI: 10.2210/pdb4leo/pdb
• Descriptor: RG7116 Fab heavy chain, RG7116 Fab light chain, Receptor tyrosine-protein kinase erbB-3, ... (6 entities in total)
• Functional Keywords: fab fragment, therapeutic antibody, her3 receptor, transferase-immune system complex, transferase/immune system
• Biological source: Mus musculus (mouse); More
• Total number of polymer chains: 3
• Total formula weight: 118509.99

Authors

Schiller, C.B.,Hopfner, K.P. (deposition date: 2013-06-26, release date: 2013-07-10, Last modification date: 2024-10-30)

Primary citation

Mirschberger, C.,Schiller, C.B.,Schraml, M.,Dimoudis, N.,Friess, T.,Gerdes, C.A.,Reiff, U.,Lifke, V.,Hoelzlwimmer, G.,Kolm, I.,Hopfner, K.P.,Niederfellner, G.,Bossenmaier, B.
RG7116, a Therapeutic Antibody That Binds the Inactive HER3 Receptor and Is Optimized for Immune Effector Activation.
Cancer Res., 73:5183-5194, 2013

PubMed Abstract: The EGF receptor (EGFR) HER3 is emerging as an attractive cancer therapeutic target due to its central position in the HER receptor signaling network. HER3 amplifies phosphoinositide 3-kinase (PI3K)-driven tumorigenesis and its upregulation in response to other anti-HER therapies has been implicated in resistance to them. Here, we report the development and characterization of RG7116, a novel anti-HER3 monoclonal antibody (mAb) designed to block HER3 activation, downregulate HER3, and mediate enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) via glycoengineering of the Fc moiety. Biochemical studies and X-ray crystallography revealed that RG7116 bound potently and selectively to domain 1 of human HER3. Heregulin binding was prevented by RG7116 at concentrations more than 1 nmol/L as was nearly complete inhibition of HER3 heterodimerization and phosphorylation, thereby preventing downstream AKT phosphorylation. In vivo RG7116 treatment inhibited xenograft tumor growth up to 90% relative to controls in a manner accompanied by downregulation of cell surface HER3. RG7116 efficacy was further enhanced in combination with anti-EGFR (RG7160) or anti-HER2 (pertuzumab) mAbs. Furthermore, the ADCC potency of RG7116 was enhanced compared with the nonglycoengineered parental antibody, both in vitro and in orthotopic tumor xenograft models, where an increased median survival was documented. ADCC degree achieved in vitro correlated with HER3 expression levels on tumor cells. In summary, the combination of strong signaling inhibition and enhanced ADCC capability rendered RG7116 a highly potent HER3-targeting agent suitable for clinical development.

PubMed: 23780344
DOI: 10.1158/0008-5472.CAN-13-0099

Experimental method

X-RAY DIFFRACTION (2.64 Å)