Peptidomimetic-based antibody surrogate for HER2

Inhibition of human epidermal growth factor receptor 2 mediated cell signaling pathway is an important therapeutic strategy for HER2-positive cancers.Although monoclonal antibodies are currently used as marketed drugs,their large molecular weight,high cost of production and susceptibility to proteolysis could be a hurdle for long-term application.In this study,we reported a strategy for the development of artificial antibody based on y-AApeptides to target HER2 extracellular domain(ECD).To achieve this,we synthesized a one-bead-two-compound(OBTC)library containing 320,000 cyclic y-AApeptides,from which we identified a y-AApeptide,M-3-6,that tightly binds to HER2 selectively.Subsequently,we designed an antibody-like dimer of M-3-6,named M-3-6-D,which showed excellent binding affinity toward HER2 comparable to monoclonal antibodies.Intriguingly,M-3-6-D was completely resistant toward enzymatic degradation.In addition,it could effectively inhibit the phosphorylation of HER2,as well as the downstream signaling pathways of AKT and ERK.Furthermore,M-3-6-D also efficiently inhibited cell proliferation in vitro,and suppressed tumor growth in SKBR3 xenograft model in vivo,implying its therapeutic potential for the treatment of cancers.Its small molecular weight,antibody-like property,resistance to proteolysis,may enable it a new generation of artificial antibody surrogate.Furthermore,our strategy of artificial antibody surrogate based on dimers of cyclicγ-AApeptides could be applied to a myriad of disease-related receptor targets in future.