Disulfide-Directed Multicylic Peptides for Targeting and Radionuclide Imaging of HER2 Expressing Tumors

Human epidermal growth factor receptor 2 (HER2) is a
critical therapeutic
target in various cancers, but its accurate noninvasive quantification
remains challenging. Existing positron emission tomography (PET) tracers,
such as antibodies and peptides, are limited by suboptimal clearance,
insufficient tumor uptake and retention, and poor proteolytic stability.
Here, we introduce a new class of disulfide-directed multicyclic peptides
(DDMPs) that combine a conformationally rigid and stable scaffold
with excellent HER2-binding properties. Using yeast display and directed
evolution, we identified optimized DDMPs with single-digit nanomolar
affinity for HER2. Alanine scanning mutagenesis revealed conserved
residues that were amenable to functional modification. After gallium-68
(68Ga) radiolabeling, these DDMPs demonstrated significantly
enhanced tumor accumulation, prolonged retention, and superior sensitivity
in detecting HER2-expressing tumors compared to those of existing
peptide tracers. Our work establishes DDMPs as a structurally distinct
class of peptide tracers with superior performance, representing a
significant advancement toward the clinical translation of precision
PET imaging for HER2-positive cancers.