Graduate Student Emily Ankrom

"Selective Display of Immuno-engagers on Tumor Cells via the pH-low Insertion Peptide"

The tendency of cancer therapies to be highly toxic and lack targeting features emphasizes the need for tumor-directed delivery strategies. The lack of specific tumor biomarkers is a major hurdle for developing targeted therapeutics. However, one feature characteristic of nearly all solid tumors is their extracellular acidity. This inherent acidity provides the basis for drug delivery via pH-low insertion peptides (pHLIPs), a family of peptides that insert in cell membranes as a transmembrane helix under acidic conditions and that are known to selectively accumulate in tumors1. The unidirectional membrane-insertion property of pHLIP allows cargoes linked to its N-terminus to be displayed on the extracellular face of the membrane. Our strategy is to use pHLIP to decorate tumor cells with immune cell engagers and facilitate killing by engineered effector cells. We have previously established that we can use pHLIP to display antigens on tumor cells, recruit antibodies, and induce killing by engineered natural killer (NK) cells2. We have explored a novel strategy to use a covalent reactive handle on pHLIP to facilitate antibody recruitment to the cancer cell surface and subsequent killing by NK cells. Lastly, we are exploring the use of antigen-pHLIP conjugates to induce the killing of tumor cells by chimeric antigen receptor T-cells (CAR-T) and CAR-NK cells.

(1) Weerakkody, D.; Moshnikova, A.; Thakur, M. S.; Moshnikova, V.; Daniels, J.; Engelman, D. M.; Andreev, O. A.; Reshetnyak, Y. K. Family of PH (Low) Insertion Peptides for Tumor Targeting. Proc. Natl. Acad. Sci. 2013, 110 (15), 5834–5839.
(2) Wehr, J.; Sikorski, E. L.; Bloch, E.; Feigman, M. S.; Ferraro, N. J.; Baybutt, T. R.; Snook, A. E.; Pires, M. M.; Thévenin, D. PH-Dependent Grafting of Cancer Cells with Antigenic Epitopes Promotes Selective Antibody-Mediated Cytotoxicity. J. Med. Chem. 2020, 63 (7), 3713–3722.