Evaluation of HER2-specific peptide ligand for its employment as radiolabeled imaging probe

Abstract

HER2 transmembrane receptor is an important target in immunotherapy treatment of breast and gastroesophageal cancer. Molecular imaging of HER2 expression may provide essential prognostic and predictive information concerning disseminated cancer and aid in selection of an optimal therapy. Radiolabeled low molecular weight peptide ligands are particularly attractive as probes for molecular imaging, since they reach and bind to the target and clear from non-target organs and blood stream faster than bulky antibodies. In this study, we evaluated a potential HER2-imaging probe, an A9 nonapeptide, derived from the trastuzumab-Fab portion. Its cellular uptake was investigated by mass spectrometry analysis of the cytoplasmic cellular extracts. Moreover, based on in-silico modeling, DTPA chelator was conjugated to N-terminus of A9. 111In-labeled A9 demonstrated nanomolar affinity to HER2-expressing BT474 cells and favorable biodistribution profile in NMRI mice. This study suggests that the peptide A9 represents a good lead candidate for development of molecular probe, to be used for imaging purposes and for the delivery of cytotoxic agents.

Peptide Based Imaging Agents for HER2 Imaging in Oncology

“…The tumors were clearly seen at all time points with a The A9 peptide was synthesized based on the design of the trastuzumab binding region and was synthesized with the chelator DTPA for labeling with 111 In, to be used as a potential HER2 imaging peptide. 29 The peptide was shown to be internalized into the BT474 cell via HER2 by mass spectrometry analysis using peptides that were bound to biotin and subsequently found within the cell lysate. Peaks associated with the peptide were found consistently within the cells.…”

Gene Expression and miRNAs Profiling: Function and Regulation in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer

“…HER2 receptor is highly expressed in human tissues including the cell membranes of epithelial cells in the gastrointestinal, respiratory, reproductive, and urinary tract as well as in the skin, breast, and placenta [29]. Amplification or overexpression of HER2 oncoprotein plays an important role in the pathogenesis of various solid tumors [30], including upper gastrointestinal tract (stomach and gastroesophageal junction adenocarcinoma) [31], ovarian cancer, colon, salivary gland [32], lung cancer, and breast cancer [33].…”

Strategic design to create HER2-targeting proteins with target-binding peptides immobilized on a fibronectin type III domain scaffold

“…11 Trastuzumab-and pertuzumab-derived peptides, QDVNTAVAW and EWVADVNPNSGGFIYNQYFK, respectively, have also been designed and used in tumor imaging. 12,13 However, their clinical application is limited to use as diagnosis probes because short peptides are very sensitive to protease activity in circulation and tissues, resulting in reduced binding to targets. Therefore, proteins with proteolysis-resistant target-binding peptides may increase the applicability of tumor-binding peptides for clinical use.…”