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

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.

Anti–CTLA-4 therapy requires an Fc domain for efficacy

“…Increasing evidence indicates a central role for FcγR in murine models. Responses to antibodies that target GITR or OX40 depend on their interactions with FcγRs, as does an IL-2–Fc fusion construct ( 24 , 38 ). Modulation of FcγR interactions dramatically enhances the efficacy of anti-CD25 antibodies in vivo ( 39 ).…”

Escherichia coli Nissle 1917 secreting functional interleukin 2 targets tumours and enhances the immune response to suppress tumours

“…However, high-dose IL-2 administration can result in severe systemic toxicity, such as malaise, fever, anasarca, jaundice, renal dysfunction and capillary leak syndrome, in many patients [32,33]. Researchers have attempted to diminish the adverse effects of systemically administered IL-2 by altering the dose, schedule and route of administration [34][35][36][37][38]. Nevertheless, the toxic effects of IL-2 therapy persist to various degrees [39].…”

Escherichia coli Nissle 1917 secreting functional interleukin 2 targets tumours and enhances the immune response to suppress tumours

“…However, high-dose IL-2 administration can result in severe systemic toxicity, such as malaise, fever, anasarca, jaundice, renal dysfunction and capillary leak syndrome, in many patients [30,31]. Researchers have attempted to diminish the adverse effects of systemically administered IL-2 by altering the dose, schedule and route of administration [32][33][34][35][36]. Nevertheless, the toxic effects of IL-2 therapy persist to various degrees [37].…”