Peptidomimetic-based antibody surrogate for HER2.

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Targeting human epidermal growth factor receptor 2 (HER2) is crucial for treating HER2-positive cancers.
• Current monoclonal antibody therapies face limitations like high cost and susceptibility to degradation.

Purpose of the Study:

• To develop a novel artificial antibody targeting the HER2 extracellular domain (ECD).
• To create a stable and effective therapeutic alternative to traditional monoclonal antibodies.

Main Methods:

• Synthesis of a large library of cyclic γ-AApeptides using a one-bead-two-compound (OBTC) approach.
• Identification and characterization of a selective HER2-binding γ-AApeptide (M-3-6) and its dimeric form (M-3-6-D).
• In vitro and in vivo evaluation of M-3-6-D's efficacy in inhibiting HER2 signaling, cell proliferation, and tumor growth.

Main Results:

• A cyclic γ-AApeptide, M-3-6, was identified with selective binding to HER2 ECD.
• The dimeric form, M-3-6-D, exhibited HER2 binding affinity comparable to monoclonal antibodies and resistance to proteolysis.
• M-3-6-D effectively inhibited HER2 phosphorylation, downstream AKT/ERK signaling, and suppressed tumor growth in vivo.

Conclusions:

• M-3-6-D represents a promising new generation of artificial antibody surrogates for HER2-targeted cancer therapy.
• The strategy of using dimeric cyclic γ-AApeptides can be extended to target other disease-related receptors.