Targeting an engineered cytokine with interleukin-2 and interleukin-15 activity to the neovasculature of solid tumors

Oncotarget
Michael R MortensenDario Neri

Abstract

There is a growing interest in the antibody-based delivery of cytokines to the tumor environment as a means to boost the anti-cancer activity of tumor-resident T cells and NK cells. Here, we describe the expression and characterization of fusion proteins, featuring the L19 antibody (specific to the alternatively-spliced EDB domain of fibronectin) and an engineered cytokine with interleukin-2 and interleukin-15 properties. The cytokine moiety was fused either at the N-terminal or at the C-terminal extremity and both fusion proteins showed a selective tumor accumulation in a quantitative biodistribution experiment. The N-terminal fusion inhibited tumor growth in immunocompetent mice bearing F9 carcinomas or WEHI-164 sarcomas when used as single agent. The anticancer activity was compared to the one of the same cytokine payload used as recombinant protein or fused to an anti-hen egg lysozyme antibody, serving as negative control of irrelevant specificity in the mouse. These results indicate that the antibody-based delivery of engineered cytokines to the tumor neovasculature may mediate a potent anticancer activity.

References

Feb 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·S D GilliesR A Reisfeld
Mar 1, 1995·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·G FyfeA C Louie
Jul 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·P HolligerG Winter
Nov 24, 1999·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·M B AtkinsS A Rosenberg
Aug 31, 2002·Cancer Immunology, Immunotherapy : CII·Stephen D GilliesKin-Ming Lo
Sep 28, 2002·International Journal of Cancer. Journal International Du Cancer·Laura BorsiLuciano Zardi
Aug 23, 2003·Blood·Laura BorsiLuciano Zardi
Nov 19, 2003·Cancer Immunology, Immunotherapy : CII·Zhengsheng YaoCynthia Sung
Jan 28, 2005·Clinical and Experimental Medicine·J S Dela CruzS L Morrison
Apr 1, 2005·International Journal of Cancer. Journal International Du Cancer·Christina EbbinghausDario Neri
Jan 31, 2007·Arthritis Research & Therapy·Eveline TrachselDario Neri
Mar 21, 2008·Nature Reviews. Cancer·Steven A RosenbergMark E Dudley
Jul 17, 2009·Blood·Carolina BergerStanley R Riddell
Jun 8, 2010·The New England Journal of Medicine·F Stephen HodiWalter J Urba
Jun 16, 2010·Proceedings of the National Academy of Sciences of the United States of America·Carsten KriegOnur Boyman
Oct 29, 2011·Trends in Pharmacological Sciences·Jason C SteelJohn C Morris
Feb 22, 2012·Nature Reviews. Immunology·Onur Boyman, Jonathan Sprent
Apr 12, 2012·Molecular Cancer Therapeutics·Vanessa KermerDafne Müller
Jun 14, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Nadine PascheDario Neri
May 17, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Tania CarmenateKalet León
Jun 8, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Steven A Rosenberg
Oct 30, 2014·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·Esther M YooSherie L Morrison
Mar 4, 2015·Proceedings of the National Academy of Sciences of the United States of America·Alice TzengK Dane Wittrup
Feb 3, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Deborah H CharychStephen K Doberstein
Dec 3, 2016·Science Translational Medicine·Natalia Arenas-RamirezOnur Boyman
Jan 13, 2017·Cancer Immunology, Immunotherapy : CII·Benjamin WeideGiuliano Elia
Jul 19, 2017·Molecular Cancer Therapeutics·Roberto De LucaDario Neri
Oct 19, 2017·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Margaret K CallahanMario Sznol
Sep 12, 2018·Advanced Drug Delivery Reviews·Cornelia Hutmacher, Dario Neri
Dec 14, 2018·Experimental & Molecular Medicine·Pramod DarvinEyad Elkord

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Methods Mentioned

BETA
size exclusion chromatography
surface plasmon resonance
flow cytometry
glycosylation
chips
flow
FACS

Clinical Trials Mentioned

NCT02938299
NCT03420014

Software Mentioned

GraphPad Prism

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