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 pro-teolysis could be a hurdle for long-term application. In this study, we reported a strategy for the devel-opment of artificial antibody based on gamma-AApeptides to target HER2 extracellular domain (ECD). To achieve this, we synthesized a one-bead-two-compound (OBTC) library containing 320,000 cyclic gamma-AA-peptides, from which we identified a gamma-AApeptide, M-3-6, that tightly binds to HER2 selectively. Sub-sequently, 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 phosphor-ylation 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 sur-rogate. Furthermore, our strategy of artificial antibody surrogate based on dimers of cyclic gamma-AApeptides could be applied to a myriad of disease-related receptor targets in future. (C) 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

Automated summary

The study developed an artificial antibody based on gamma-AApeptides, with small molecular weight, antibody-like properties, strong resistance to proteolysis, excellent binding affinity to HER2, effective inhibition of cell proliferation in vitro, suppression of tumor growth in vivo, and potential therapeutic applications for treating cancers.