PDBsum entry 4leo

Transferase/immune system

PDB id: 4leo

Contents

Protein chains

214 a.a.

219 a.a.

601 a.a.

Ligands

NAG-NAG

NAG ×5

Waters ×150

PDB id:

4leo

Name:

Transferase/immune system

Title:

Crystal structure of anti-her3 fab rg7116 in complex with the extracellular domains of human her3 (erbb3)

Structure:

Rg7116 fab heavy chain. Chain: a. Engineered: yes. Rg7116 fab light chain. Chain: b. Engineered: yes. Receptor tyrosine-protein kinase erbb-3. Chain: c. Fragment: unp residues 20-631.

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Homo sapiens. Human. Organism_taxid: 9606. Gene: erbb3, her3.

Resolution:

2.64Å R-factor: 0.230 R-free: 0.258

Authors:

C.B.Schiller,K.P.Hopfner

Key ref:

C.Mirschberger et al. (2013). RG7116, a therapeutic antibody that binds the inactive HER3 receptor and is optimized for immune effector activation. Cancer Res, 73, 5183-5194. PubMed id: 23780344 DOI: 10.1158/0008-5472.CAN-13-0099

Date:

26-Jun-13 Release date: 10-Jul-13

Protein chain

No UniProt id for this chain

Struc: 214 a.a.

Protein chain

No UniProt id for this chain

Struc: 219 a.a.

Protein chain

P21860  (ERBB3_HUMAN) -  Receptor tyrosine-protein kinase erbB-3 from Homo sapiens

Seq: 1342 a.a.

Struc: 601 a.a.

Enzyme reactions

• Enzyme class: Chain C: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

L-tyrosyl-[protein] + ATP (Bound ligand (Het Group name = NAG) matches with 47.62% similarity) = O-phospho-L-tyrosyl-[protein] + ADP + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1158/0008-5472.CAN-13-0099

Cancer Res 73:5183-5194 (2013)

PubMed id: 23780344

RG7116, a therapeutic antibody that binds the inactive HER3 receptor and is optimized for immune effector activation.

C.Mirschberger, C.B.Schiller, M.Schräml, N.Dimoudis, T.Friess, C.A.Gerdes, U.Reiff, V.Lifke, G.Hoelzlwimmer, I.Kolm, K.P.Hopfner, G.Niederfellner, B.Bossenmaier.

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. Cancer Res; 73(16); 5183-94. ©2013 AACR.