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Potent antitumour activity of interleukin-2-Fc fusion proteins requires
Fc-mediated depletion of regulatory T-cells
#MMPMID28497796
Vazquez-Lombardi R
; Loetsch C
; Zinkl D
; Jackson J
; Schofield P
; Deenick EK
; King C
; Phan TG
; Webster KE
; Sprent J
; Christ D
Nat Commun
2017[May]; 8
(?): 15373
PMID28497796
show ga
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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