Oncotarget

Research Papers:

Targeted enhancement of the therapeutic window of L19-TNF by transient and selective inhibition of RIPK1-signaling cascade

Sheila Dakhel, Tiziano Ongaro, Baptiste Gouyou, Mattia Matasci, Alessandra Villa, Dario Neri and Samuele Cazzamalli

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Oncotarget. 2019; 10:6678-6690. https://doi.org/10.18632/oncotarget.27320

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Abstract

Sheila Dakhel1, Tiziano Ongaro1, Baptiste Gouyou1, Mattia Matasci1, Alessandra Villa1, Dario Neri2 and Samuele Cazzamalli1,*

1 Philochem AG, Otelfingen CH-8112, Switzerland

2 Department of Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), CH-8093 Zurich, Switzerland

* Corresponding author

Correspondence to:

Samuele Cazzamalli,email: samuele.cazzamalli@philogen.com

Keywords: tumor targeting; antibody-cytokine fusions; targeted-tumor necrosis factor; EDB-fibronectin; intracellular RIPK1-inhibitors

Received: August 05, 2019     Accepted: October 19, 2019     Published: November 19, 2019

ABSTRACT

Introduction

Cytokine-based products are gaining importance for cancer immunotherapy. L19-TNF is a clinical-stage antibody-cytokine fusion protein that selectively accumulates to tumors and displays potent anticancer activity in preclinical models. Here, we describe an innovative approach to transiently inhibit off-target toxicity of L19-TNF, while maintaining antitumor activity.

Methods

GSK’963, a potent small molecule inhibitor of RIPK1, was tested in tumor-bearing mice for its ability to reduce acute toxicity associated with TNF signaling. The biological effects of L19-TNF on tumor cells, lymphocytes and tumor vessels were investigated with the aim to enable the administration of TNF doses, which would otherwise be lethal.

Results

Transient inhibition of RIPK1 allowed to increase the maximal tolerated dose of L19-TNF. The protective effect of GSK’963 did not affect the selective localization of the immunocytokine to tumors as evidenced by quantitative biodistribution analysis and allowed to reach high local TNF concentrations around tumor blood vessels, causing diffused vascular shutdown and hemorrhagic necrosis within the neoplastic mass.

Conclusions

The selective inhibition of RIPK1 with small molecule inhibitors can be used as a pharmaceutical tool to transiently mask TNF activity and improve the therapeutic window of TNF-based biopharmaceuticals. Similar approaches may be applicable to other pro-inflammatory cytokines.


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