Potent antitumour activity of IL-2-Fc fusion proteins requires Fc-mediated depletion of regulatory T-cells
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.
|Authors||Vazquez-Lombardi,R; Loetsch, C; Zinkl,D; Jackson,J; Schofield, P; Deenick, EK; King,C; Phan, T; Webster, KE; Sprent, J; Christ,C|
|Responsible Garvan Author|
|Publisher Name||Nature Communications|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/28497796|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/14054|