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Paracrine delivery of therapeutic biologics for cancer

Smith, S. N. and Schubert, R. and Simic, B. and Brücher, D. and Schmid, M. and Gradinaru, V. and Plückthun, A. (2019) Paracrine delivery of therapeutic biologics for cancer. Human Gene Therapy, 30 (11). A3. ISSN 1043-0342.

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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.

Item Type:Article
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Gradinaru, V.0000-0001-5868-348X
Additional Information:© 2019 Mary Ann Liebert, Inc., publishers. Published Online: 7 Nov 2019.
Issue or Number:11
Record Number:CaltechAUTHORS:20191216-134424777
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Official Citation:ESGCT 27th Annual Congress In collaboration with SETGyc Barcelona, Spain October 22–25, 2019 Abstracts. Human Gene Therapy 2019 30:11, A1-A221; doi: 10.1089/hum.2019.29095.abstracts
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:100305
Deposited By: Tony Diaz
Deposited On:16 Dec 2019 22:02
Last Modified:16 Dec 2019 22:21

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