Potent antitumour activity of interleukin-2-Fc fusion proteins requires Fc-mediated depletion of regulatory T-cells

Nature Communications
Rodrigo Vazquez-LombardiDaniel Christ

Abstract

Interleukin-2 (IL-2) is an established therapeutic agent used for cancer immunotherapy. Since treatment efficacy is mediated by CD8+ and NK cell activity at the tumour site, considerable efforts have focused on generating variants that expand these subsets systemically, as exemplified by IL-2/antibody complexes and 'superkines'. Here we describe a novel determinant of antitumour activity using fusion proteins consisting of IL-2 and the antibody fragment crystallizable (Fc) region. Generation of long-lived IL-2-Fc variants in which CD25 binding is abolished through mutation effectively prevents unwanted activation of CD25+ regulatory T-cells (Tregs) and results in strong expansion of CD25- cytotoxic subsets. Surprisingly, however, such variants are less effective than wild-type IL-2-Fc in mediating tumour rejection. Instead, we report that efficacy is crucially dependent on depletion of Tregs through Fc-mediated immune effector functions. Our results underpin an unexpected mechanism of action and provide important guidance for the development of next generation IL-2 therapeutics.

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Citations

Dec 15, 2017·Nature Protocols·Rodrigo Vazquez-LombardiDaniel Christ
May 2, 2019·The Journal of Experimental Medicine·Zinan ZhangMichael J Lenardo
Jan 11, 2019·Nature·Daniel-Adriano SilvaDavid Baker
Aug 10, 2018·Nature Reviews. Immunology·Rosanne SpolskiWarren J Leonard
Nov 10, 2018·Nature Communications·Zuqiang LiuDavid L Bartlett
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Mar 4, 2021·Bioconjugate Chemistry·Mengxin QianJun Feng
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Sep 20, 2019·ACS Applied Materials & Interfaces·Wenquan OuJong Oh Kim

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Methods Mentioned

BETA
biosensor
transgenic
flow cytometry
biosensors
chips

Software Mentioned

BIAevaluation
GeneArt

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