5o4o
HER3 in complex with Fab MF3178
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 PubMedHER2-driven cancers require phosphatidylinositide-3 kinase (PI3K)/Akt signaling through HER3 to promote tumor growth and survival. The therapeutic benefit of HER2-targeting agents, which depend on PI3K/Akt inhibition, can be overcome by hyperactivation of the heregulin (HRG)/HER3 pathway. Here we describe an unbiased phenotypic combinatorial screening approach to identify a bispecific immunoglobulin G1 (IgG1) antibody against HER2 and HER3. In tumor models resistant to HER2-targeting agents, the bispecific IgG1 potently inhibits the HRG/HER3 pathway and downstream PI3K/Akt signaling via a "dock & block" mechanism. This bispecific IgG1 is a potentially effective therapy for breast cancer and other tumors with hyperactivated HRG/HER3 signaling. Unbiased Combinatorial Screening Identifies a Bispecific IgG1 that Potently Inhibits HER3 Signaling via HER2-Guided Ligand Blockade.,Geuijen CAW, De Nardis C, Maussang D, Rovers E, Gallenne T, Hendriks LJA, Visser T, Nijhuis R, Logtenberg T, de Kruif J, Gros P, Throsby M Cancer Cell. 2018 May 14;33(5):922-936.e10. doi: 10.1016/j.ccell.2018.04.003. PMID:29763625[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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