Structural Optimization and Radiolabeling of EphA2-Targeted Bicyclic Peptides for Tumor Theranostics

Area of Science:

• Biochemistry
• Molecular Biology
• Radiochemistry

Background:

• Ephrin type-A receptor 2 (EphA2) is overexpressed in aggressive cancers, making it a key theranostic target.
• Developing targeted agents for EphA2 is crucial for advancing cancer diagnostics and therapeutics.

Purpose of the Study:

• To optimize a bicyclic peptide scaffold for high-affinity EphA2 targeting.
• To develop and evaluate DOTA-conjugated radiotracers for EphA2-positive malignancies.
• To assess the theranostic potential of the optimized peptide for imaging and radionuclide therapy.

Main Methods:

• Systematic optimization of the BCY6088 bicyclic peptide scaffold led to the high-affinity ligand Pep-34 (K_D = 3.6 nM).
• Development of three DOTA-conjugated radiotracers: ⁶⁸Ga-Pep-36, ⁶⁸Ga-Pep-37, and ⁶⁸Ga-Pep-38.
• In vivo evaluation of radiotracers in HeLa-EphA2^OE xenografts and therapeutic assessment using ¹⁷⁷Lu-Pep-38.

Main Results:

• ⁶⁸Ga-Pep-38 demonstrated optimal diagnostic properties, including good serum stability and tumor targeting efficiency (SUV = 1.8 at 60 min).
• ¹⁷⁷Lu-Pep-38 treatment resulted in significant, dose-dependent tumor growth inhibition (up to 98.5%) without detectable toxicity.
• Pep-38 proved effective for both molecular imaging and targeted radionuclide therapy.

Conclusions:

• Pep-38 is a highly promising bicyclic peptide theranostic agent for EphA2-overexpressed malignancies.
• The developed radiotracers enable precise molecular imaging and targeted radionuclide therapy.
• Pep-38 offers a potential new strategy for precision oncology in EphA2-driven cancers.