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

Rodrigo Vazquez-Lombardi, Claudia Loetsch, Daniela Zinkl, Jennifer Jackson, Peter Schofield, Elissa K. Deenick, Cecile King, Tri Giang Phan, Kylie E. Webster, Jonathan Sprent () and Daniel Christ ()
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Rodrigo Vazquez-Lombardi: Garvan Institute of Medical Research
Claudia Loetsch: Garvan Institute of Medical Research
Daniela Zinkl: Garvan Institute of Medical Research
Jennifer Jackson: Garvan Institute of Medical Research
Peter Schofield: Garvan Institute of Medical Research
Elissa K. Deenick: Garvan Institute of Medical Research
Cecile King: Garvan Institute of Medical Research
Tri Giang Phan: Garvan Institute of Medical Research
Kylie E. Webster: Garvan Institute of Medical Research
Jonathan Sprent: Garvan Institute of Medical Research
Daniel Christ: Garvan Institute of Medical Research

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15373

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