Abstract 1499: SUPR peptides as novel targeted molecular imaging agents for Her2

Ideal molecular imaging agents would combine the affinity and selectivity of monoclonal antibodies with the rapid clearance and pharmacokinetics of small molecules Here we describe the use of directed evolution to design Scanning Unnatural Protease Resistant (SUPR) peptides as novel molecular scaffolds for in vivo optical and PET imaging of the Her2 receptor. SUPR peptides were obtained through selection against Her2-expressing breast cancer cells in culture using focused biological display peptide libraries pre-selected for protease resistance. SUPR peptide libraries were programmed with unnatural amino acids for enhanced stability and chemically cyclized after translation to enhance affinity. Peptides isolated from selection selectively bind the Her2 receptor in vitro with low nanomolar affinity and do not compete with Trastuzumab or Pertuzumab. Cy5-labeled SUPR peptides show rapid and Her2-specific tumor uptake in vivo and minimal retention in non-tumor tissues after 24 hours of washout. SUPR peptides can be efficiently labeled with 18F via the copper-catalyzed azide-alkyne cycloaddtion and the resulting radiotracers used for nuclear imaging of Her2-postive tumors by PET/CT. Unlike antibodies and their derivatives, SUPR peptides are synthesized chemically and show rapid clearance from systemic circulation. SUPR peptides also show dramatically enhanced stability relative to linear peptides obtained from phage display or combinatorial chemistry while still retaining affinities compatible with molecular imaging applications. While SUPR peptides are selected from biological display libraries, they share similar chemical composition and structure with peptides derived from non-ribosomal peptide synthesis. We believe that this combination of affinity, stability, evolvability, and synthetic accessibility make SUPR peptide technology a general approach for generating highly potent compounds for targeted molecular imaging of cancer biomarkers. Citation Format: Lindsay Kelderhouse, Amanda Hardy, Terry T. Takahashi, Argentina Ornelas, Seth Gammon, Shannon Howell, Peiying Yang, Pin Wang, Richard W. Roberts, Steve Fiacco, Steven W. Millward. SUPR peptides as novel targeted molecular imaging agents for Her2. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1499. doi:10.1158/1538-7445.AM2015-1499