Paracrine delivery of therapeutic biologics for cancer

Abstract

A fundamental goal of cancer drug delivery is to achieve sufficient levels within the tumour without leading to high systemic concentrations that might cause off-target toxicities. In situ production of protein-based therapeutics by tumour cells provides an attractive alternative to treatment with repeated high bolus injections, as secretion by the tumour itself could provide high local concentrations that act in a paracrine fashion over an extended duration. For this purpose, we have developed a non-oncolytic adenoviral delivery system that allows for targeting of Ad5 to discrete cell types by redirecting viral tropism to cell surface biomarkers through the use of interchangeable adapters. Furthermore, we recently described the engineering of a protein-based 'shield' that is coated on the Ad5 capsid, which, together with the retargeting adapters, allows for improved tumour specificity and prevention of viral clearance. To test this delivery strategy in vivo, SCID-beige mice bearing orthotopic BT474 xenografts were treated with three doses of either a cancerspecific, non-replicative Ad5 that encodes a secreted anti-HER2 antibody, trastuzumab, in its genome, or with the protein therapeutic itself (Herceptin®). We have employed state-of-the-art whole tumour clearing and imaging with confocal microscopy at high spatial resolution in 3D to assess biodistribution, and large volumetric imaging has revealed that the secreted therapeutic diffuses significantly throughout the tumour leading to a therapeutic effect and delayed tumour outgrowth. Moreover, the systemic concentration of antibody is significantly reduced with viral delivery, suggesting that paracrine delivery may be a promising strategy for delivery of biologics with narrow therapeutic indices.

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