Oncotarget

Research Papers:

A novel format for recombinant antibody-interleukin-2 fusion proteins exhibits superior tumor-targeting properties in vivo

Tiziano Ongaro, Baptiste Gouyou, Marco Stringhini, Riccardo Corbellari, Dario Neri _ and Alessandra Villa _

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Oncotarget. 2020; 11:3698-3711. https://doi.org/10.18632/oncotarget.27726

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Abstract

Tiziano Ongaro1,2, Baptiste Gouyou1, Marco Stringhini3, Riccardo Corbellari1,4, Dario Neri3 and Alessandra Villa1

1 Philochem AG, Otelfingen, Switzerland

2 University School for Advanced Studies IUSS Pavia, Pavia, Italy

3 Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, ETH Zürich, Zürich, Switzerland

4 University of Trento, CiBIO, Department of Cellular, Computational and Integrative Biology, Trento, Italy

Correspondence to:

Dario Neri,email: dario.neri@pharma.ethz.ch
Alessandra Villa,email: alessandra.villa@philogen.com

Keywords: tumor targeting; fibronectin; immunocytokines; interleukin-2; protein engineering

Received: June 11, 2020     Accepted: August 17, 2020     Published: October 13, 2020

Copyright: © 2020 Ongaro et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

The targeted delivery of interleukin-2 to the tumor is gaining attention as an avenue to potentiate the action of T and NK cells at the site of disease. We have previously described the fusion of the L19 antibody, specific to the EDB domain of fibronectin, with human interleukin-2, using a non-covalent homodimeric diabody format. Here, we describe four novel formats for the L19-IL2 fusion, featuring different arrangements of antibody and IL2. A comparative quantitative biodistribution analysis in tumor-bearing mice using radioiodinated proteins revealed that the novel format (L19L19-IL2, with the antibody in single-chain diabody format) exhibited the best biodistribution results. In vitro assays on peripheral blood mononuclear cells showed a decrease activation of regulatory T cells when single IL2 domain was used. In vivo, both L19-IL2 and L19L19-IL2 inhibited tumor growth in immunocompetent mouse models of cancer. T-cell analysis revealed similar levels of CD4+ and FoxP3+ cells, with an expansion of the CD8+ T cell in mice treated with L19-IL2 and L19L19-IL2. The percentage of CD4+ regulatory T cells was markedly decreased with L19L19-IL2 combined with a mouse-specific PD-1 blocker. Collectively, these data indicate that the new L19L19-IL2 format exhibits favorable tumor-homing properties and mediates a potent anti-cancer activity in vivo.


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