Targeting an engineered cytokine with interleukin-2 and interleukin-15 activity to the neovasculature of solid tumors
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Michael R. Mortensen1, Jacqueline Mock1, Marco Bertolini1, Marco Stringhini1, Marco Catalano1 and Dario Neri1
1 Department of Chemistry and Applied Biosciences (D-CHAB), Institute for Pharmaceutical Sciences (IPW), 8093 Zurich, Switzerland
|Michael R. Mortensen,||email:||[email protected]|
Keywords: immunotherapy; immunocytokines; EDB of fibronectin; antibody-cytokine fusion proteins; engineered cytokine
Received: July 30, 2020 Accepted: September 24, 2020 Published: November 03, 2020
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.
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