Abstract A102: pHLIP technology for targeting acidity at surface of tumor cells and extracellular and intracellular delivery of imaging and therapeutic agents

Abstract

Abstract pH-Low Insertion Peptides (pHLIP® peptides) are a platform technology for targeting of acidity at the surface of individual cells within tumors. Most proteins that are located across membranes have one or more helical segments that cross the lipid bilayer, and studies of these membrane proteins revealed pHLIPs, which could fold from disorganized (unstructured) states outside of a membrane to form a helix across the membrane in response to local acidity. Because tumor cell surfaces are acidic as a result of their active metabolism, versions of pHLIP® peptides were extensively investigated and tested as possible tumor targeting agents. Our studies showed that an extensive variety of cargoes can be targeted to cell surfaces and that a surprising range of cargoes can be delivered across membranes into cells if their surfaces are acidic, creating opportunities to detect and treat tumors. pHLIP® peptides can be used to target and tether cargo molecules to the surfaces of cells in low pH environments of acidic diseased tissues. The cargo can be an optical marker, a PET, a SPECT, or a MR imaging agent, or an antigen or a protein delivered to induce certain cellular or immune responses. We are translating pHLIP®-based imaging agents to the clinic for diagnostic PET imaging, fluorescence-guided surgical procedures and photo-acoustic pre-operative imaging. pHLIP® peptides can also be used for the intracellular delivery of payloads, facilitating the translocation of therapeutic cargoes across the membranes of cells with low extracellular pH, such as those cells found in acidic diseased tissue. These payloads are conjugated to the membrane-inserting end of pHLIP® peptide, typically via a link that is unstable inside the cell. Thus, pHLIP® peptide targets a payload to acidic diseased cells and flips the cargo across the plasma membrane, releasing it in the cytoplasm. Therapeutic cargoes may include toxins, metabolic activators/inhibitors, chemotherapeutic agents, or agents to alter gene expression. *YKR, OAA, and DME are founders of pHLIP, Inc. and have financial interests in the company. Citation Format: Yana K Reshetnyak, Oleg A Andreev, Donald Engelman. pHLIP technology for targeting acidity at surface of tumor cells and extracellular and intracellular delivery of imaging and therapeutic agents [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A102. doi:10.1158/1535-7163.TARG-19-A102