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.
Highlights
Interleukin-2 (IL-2) is an established therapeutic agent used for cancer immunotherapy
To reduce binding of our IL-2-fragment crystallizable (Fc) construct to CD25 þ cells, we introduced mutations directed at disrupting the IL-2/CD25 interaction (Fig. 1a, Supplementary Fig. 1)
We found that IL-2-Fc proteins targeted a low proportion of total CD8 þ T-cells, which is consistent with only a small fraction of this compartment
Summary
Interleukin-2 (IL-2) is an established therapeutic agent used for cancer immunotherapy. Generation of long-lived IL-2-Fc variants in which CD25 binding is abolished through mutation effectively prevents unwanted activation of CD25 þ regulatory T-cells (Tregs) and results in strong expansion of CD25 À cytotoxic subsets. Such variants are less effective than wild-type IL-2-Fc in mediating tumour rejection. The potent antitumour activity observed in a subset of patients led to the regulatory approval of a high-dose recombinant IL-2 formulation for cancer immunotherapy of metastatic renal cancer in 1992 and for metastatic melanoma in 1998 In addition to the undesired promotion of Treg proliferation, clinical use of IL-2 is further complicated by a short serum half-life (B7 min) and dose-limiting toxicities[10,11]
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