Cytokines fused to antibodies and their combinations as therapeutic agents against different peritoneal HER2/neu expressing tumors

Molecular Cancer Therapeutics
Gustavo HelgueraManuel L Penichet

Abstract

We have previously generated antihuman HER2/neu-humanized IgG3 fused to interleukin-2 (IL-2), IL-12, or granulocyte macrophage colony-stimulating factor (GM-CSF) [monofunctional fusion proteins (mono-AbFP)] or fused to IL-2 and IL-12 or IL-12 and GM-CSF [bifunctional fusion proteins (bi-AbFP)]. These AbFPs retained cytokine and antigen-binding activities. We have now further characterized the AbFPs and determined the heparin-binding activity of the fused cytokines, their ability to trigger IFN-gamma secretion and natural killer (NK) activation, and their direct antitumor efficacy. Flow cytometry revealed heparin-binding activity in the AbFPs containing IL-12 and IL-2, although this activity seems to be decreased in the bi-AbFPs. However, both bi-AbFPs retained the capacity to stimulate IL-12-dependent IFN-gamma secretion in the NK cell line KY-1, and IL-12/IL-2 bi-AbFP induced NK activity in splenocytes. The antitumor effectiveness of bi-AbFPs and mono-AbFP combinations was studied in mice challenged i.p. with three different human HER2/neu murine syngeneic models (D2F2/E2, CT26-HER2/neu, and MC38-HER2/neu). Although a significant variability in the profile of antitumor response was observed in the different tumor models, the c...Continue Reading

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Citations

Dec 24, 2011·Cancer Immunology, Immunotherapy : CII·Tracy R DanielsManuel L Penichet
Apr 15, 2008·Expert Opinion on Biological Therapy·Elizabeth Ortiz-SánchezManuel L Penichet
Feb 1, 2009·Expert Opinion on Drug Discovery·Chien-Hsing ChangDavid M Goldenberg
Aug 31, 2007·Expert Opinion on Biological Therapy·Roy Jefferis
Mar 24, 2012·Experimental Cell Research·Fatemeh Rahimi JamnaniZahra Sharifzadeh
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Mar 1, 2016·Pleura and Peritoneum·Félix GremonprezWim Ceelen
Nov 13, 2020·Frontiers in Immunology·Khue G NguyenDavid A Zaharoff

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