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The SHREAD gene therapy platform for paracrine delivery improves tumor localization and intratumoral effects of a clinical antibody

Smith, Sheena N. and Schubert, Rajib and Simic, Branko and Brücher, Dominik and Schmid, Markus and Kirk, Niels and Freitag, Patrick C. and Gradinaru, Viviana and Pluckthun, Andreas (2021) The SHREAD gene therapy platform for paracrine delivery improves tumor localization and intratumoral effects of a clinical antibody. Proceedings of the National Academy of Sciences of the United States of America, 118 (21). Art. No. e2017925118. ISSN 0027-8424. PMCID PMC8166199. https://resolver.caltech.edu/CaltechAUTHORS:20210519-141318892

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Abstract

The goal of cancer-drug delivery is to achieve high levels of therapeutics within tumors with minimal systemic exposure that could cause toxicity. Producing biologics directly in situ where they diffuse and act locally is an attractive alternative to direct administration of recombinant therapeutics, as secretion by the tumor itself provides high local concentrations that act in a paracrine fashion continuously over an extended duration (paracrine delivery). We have engineered a SHielded, REtargeted ADenovirus (SHREAD) gene therapy platform that targets specific cells based on chosen surface markers and converts them into biofactories secreting therapeutics. In a proof of concept, a clinically approved antibody is delivered to orthotopic tumors in a model system in which precise biodistribution can be determined using tissue clearing with passive CLARITY technique (PACT) with high-resolution three-dimensional imaging and feature quantification within the tumors made transparent. We demonstrate high levels of tumor cell–specific transduction and significant and durable antibody production. PACT gives a localized quantification of the secreted therapeutic and allows us to directly observe enhanced pore formation in the tumor and destruction of the intact vasculature. In situ production of the antibody led to an 1,800-fold enhanced tumor-to-serum antibody concentration ratio compared to direct administration. Our detailed biochemical and microscopic analyses thus show that paracrine delivery with SHREAD could enable the use of highly potent therapeutic combinations, including those with systemic toxicity, to reach adequate therapeutic windows.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1073/pnas.2017925118DOIArticle
https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2017925118/-/DCSupplementalPublisherSupporting Information
ORCID:
AuthorORCID
Smith, Sheena N.0000-0002-2162-7107
Simic, Branko0000-0002-7314-3913
Brücher, Dominik0000-0002-3160-5542
Schmid, Markus0000-0002-4533-371X
Freitag, Patrick C.0000-0001-8803-6048
Gradinaru, Viviana0000-0001-5868-348X
Pluckthun, Andreas0000-0003-4191-5306
Additional Information:© 2021 Published under the PNAS license. Edited by Rakesh K. Jain, Massachusetts General Hospital, Boston, MA, and approved March 18, 2021 (received for review September 10, 2020) We acknowledge Gery Barmettler and the Center for Microscopy and Image Analysis at the University of Zürich for assistance with transmission electron microscopy, Serge Chesnov and the Functional Genomics Center Zurich for assistance with mass spectrometry, Polina Zaytseva for assistance in cloning the Ad-TdTomato reporter virus, Karen Patricia Hartmann and Julien Weber for assisting with animal sample collection, Junho Hur (Kyung Hee University) for microscopy time, Gerard M. Coughlin and Alon Greenbaum (California Institute of Technology) for assistance with PACT clearing and vasculature staining protocols, Bernadetta Tarigan for animal study statistics consulting, and the following individuals for helpful discussions: Alfred Zippelius, Nicole Kirchhammer and Abhishek Kashyap (University Hospital Basel); Urs Greber, Maarit Suomalainen, and Birgit Dreier (University of Zürich); David Baltimore (California Institute of Technology); and Uwe Zangemeister (University of Bern). This research is supported by the Swiss National Science Foundation Sinergia Grant 170929 (to A.P.), National Cancer Institute of the NIH under Award Number F32CA189372 (to S.N.S.), the University of Zurich Forschungskredit 2017 ID 3761 (to D.B.), and the Vallee Foundation (to V.G.). Data Availability. All study data are included in the article and/or supporting information. S.N.S. and R.S. contributed equally to this work. B.S. and D.B. contributed equally to this work. Author contributions: S.N.S., R.S., and A.P. designed research; S.N.S., R.S., B.S., D.B., and N.K. performed research; D.B., M.S., P.C.F., and V.G. contributed new reagents/analytic tools; S.N.S., R.S., B.S., and A.P. analyzed data; and S.N.S. and A.P. wrote the paper. The authors declare no competing interest. This article is a PNAS Direct Submission. This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2017925118/-/DCSupplemental.
Funders:
Funding AgencyGrant Number
Swiss National Science Foundation (SNSF)170929
NIH Postdoctoral FellowshipF32CA189372
Universität Zürich2017 ID 3761
Vallee FoundationUNSPECIFIED
National Cancer InstituteUNSPECIFIED
Issue or Number:21
PubMed Central ID:PMC8166199
Record Number:CaltechAUTHORS:20210519-141318892
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210519-141318892
Official Citation:The SHREAD gene therapy platform for paracrine delivery improves tumor localization and intratumoral effects of a clinical antibody Sheena N. Smith, Rajib Schubert, Branko Simic, Dominik Brücher, Markus Schmid, Niels Kirk, Patrick C. Freitag, Viviana Gradinaru, Andreas Plückthun Proceedings of the National Academy of Sciences May 2021, 118 (21) e2017925118; DOI: 10.1073/pnas.2017925118
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:109187
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:21 May 2021 14:07
Last Modified:18 Aug 2021 16:54

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