¹⁷⁷Lu-labeled HER2/neu-derived peptide: A potential candidate for the targeting of HER2/neu expressing breast cancer

Objectives The high expression of HER2/neu receptor on various human cancers including breast and ovarian cancer and relatively low expression on normal human tissues makes this tumor-antigen an attractive molecular target for imaging and therapy of HER2/neu-expressing cancers. In an attempt to develop a tumor-antigen derived peptide for breast cancer imaging/treatment, 68Ga/177Lu-labeled HER2/neu-derived peptide was prepared and evaluated.

Methods The HER2/neu peptide (DOTA-Glu-Lys-Ile-Phe-Gly-Ser-Leu-Ala-Phe-Leu-NH2) was synthesized by solid-phase peptide synthesis following Fmoc/HBTU chemistry. DOTA was added to the targeting peptide at the end of solid-phase synthesis by manual conjugation. Labeling of DOTA-HER2/neu with Lu-177 was achieved in the presence of 2.5M NaOAc buffer. In vitro tumor cell binding was performed on HER2/neu expressing SKBR3 breast cancer cells and in vivo animal biodistribution/biokinetics was carried out on balb/c mice.

Results Mass spectrometry and HPLC analysis were used to confirm the structure and purity of the tumor-antigen peptide. HPLC analysis showed that the HER2/neu peptide labeled efficiently with 177Lu with high labeling efficiency (>98%). The radiopeptide displayed a high chemical resistant to DTPA transchelation and a high metabolic stability in human plasma. The radiolabeled peptide exhibited high binding affinity to HER2/neu expressing SKBR3 cells (Kd=<10nM). The radioactivity internalized into SKBR3 cells was 20%. In vivo biodistribution in balb/c mice can be characterized by an efficient clearance from the blood and elimination by both the renal and hepatobiliary routes. The uptake in the major body organs, such as the lungs, liver, stomach, kidneys and intestines was low (<6% ID/g).

Conclusions Our preliminary data indicates that 68Ga/177Lu-DOTA-HER2/neu peptide can be useful for both diagnosis and treatment of HER2/neu positive cancers. A comprehensive evaluation is in progress in order to determine the real potential of this new an attractive class of peptides for the targeting of human tumors.

Research Support Partially funded by International Atomic Energy Agency.