Enhancing the antitumor efficacy of a cell-surface death ligand by covalent membrane display
Abstract
A recombinant soluble version of the transmembrane death ligand Apo2L/TRAIL has shown compelling preclinical results as a potential cancer therapeutic, but studies in cancer patients have demonstrated little efficacy. Supported membrane display of Apo2L/TRAIL, to mimic the endogenous ligand more faithfully, markedly augments receptor clustering and apoptosis stimulation in cancer cells. Covalent attachment of Apo2L/TRAIL to the surface of liposomes offers a therapeutically tractable approach to membrane display that substantially increases tumor exposure, caspase activation, and antitumor potency. These findings open new avenues for clinical investigation of Apo2L/TRAIL as a cancer therapeutic and may apply to other members of the TNF superfamily, such as FasL and CD70, which are expressed on immune-cell surfaces and are important candidates for cancer immunotherapy.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- May 2015
- DOI:
- 10.1073/pnas.1418962112
- Bibcode:
- 2015PNAS..112.5679N