4leo | pdb_00004leo
Crystal structure of anti-HER3 Fab RG7116 in complex with the extracellular domains of human Her3 (ERBB3)
Structural highlights
DiseaseERBB3_HUMAN Defects in ERBB3 are the cause of lethal congenital contracture syndrome type 2 (LCCS2) [MIM:607598; also called Israeli Bedouin multiple contracture syndrome type A. LCCS2 is an autosomal recessive neurogenic form of a neonatally lethal arthrogryposis that is associated with atrophy of the anterior horn of the spinal cord. The LCCS2 syndrome is characterized by multiple joint contractures, anterior horn atrophy in the spinal cord, and a unique feature of a markedly distended urinary bladder. The phenotype suggests a spinal cord neuropathic etiology.[1] FunctionERBB3_HUMAN Binds and is activated by neuregulins and NTAK.[2] Publication Abstract from PubMedThe epidermal growth factor receptor HER3 is emerging as an attractive cancer therapeutic target due to its central position in the HER receptor signaling network. HER3 amplifies 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 designed to block HER3 activation, downregulate HER3, and mediate enhanced antibody-dependent cellular 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 >1 nM 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) monoclonal antibodies. Further, the ADCC potency of RG7116 was enhanced compared with the non-glycoengineered 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. RG7116, a therapeutic antibody that binds the inactive HER3 receptor and is optimized for immune effector activation.,Mirschberger C, Schiller CB, Schraml M, Dimoudis N, Friess T, Gerdes CA, Reiff U, Lifke V, Hoelzlwimmer G, Kolm I, Hopfner KP, Niederfellner G, Bossenmaier B Cancer Res. 2013 Jun 18. PMID:23780344[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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