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2018 ; 9
(ä): 1614
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Glyco-Engineered Anti-Human Programmed Death-Ligand 1 Antibody Mediates Stronger
CD8 T Cell Activation Than Its Normal Glycosylated and Non-Glycosylated
Counterparts
#MMPMID30061887
Goletz C
; Lischke T
; Harnack U
; Schiele P
; Danielczyk A
; Rühmann J
; Goletz S
Front Immunol
2018[]; 9
(ä): 1614
PMID30061887
show ga
The programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis plays a
central role in suppression of anti-tumor immunity. Blocking the axis by
targeting PD-L1 with monoclonal antibodies is an effective and already clinically
approved approach to treat cancer patients. Glyco-engineering technology can be
used to optimize different properties of monoclonal antibodies, for example,
binding to Fc?Rs. We generated two glycosylation variants of the same anti-PD-L1
antibody: one bearing core fucosylated N-glycans in its Fc part (92%) and its
de-fucosylated counterpart (4%). The two glycosylation variants were compared to
a non-glycosylated commercially available anti-PD-L1 antibody in various assays.
No differences were observed regarding binding to PD-L1 and blocking of this
interaction with its counter receptors PD-1 or CD80. The de-fucosylated
anti-PD-L1 antibody showed increased Fc?RIIIa binding resulting in enhanced
antibody dependent cellular cytotoxicity (ADCC) activity against PD-L1(+) cancer
cells compared to the "normal"-glycosylated variant. Both glycosylation variants
showed no antibody-mediated lysis of B cells and monocytes. The non-glycosylated
reference antibody showed no Fc?RIIIa engagement and no ADCC activity. Using
mixed leukocyte reaction it was observed that the de-fucosylated anti-PD-L1
antibody induced the strongest CD8 T cell activation determined by expression of
activation markers, proliferation, and cytotoxicity against cancer cells. The
systematic comparison of anti-PD-L1 antibody glycosylation variants with
different Fc-mediated potencies demonstrates that our glyco-optimization approach
has the potential to enhance CD8 T cell-mediated anti-tumor activity which may
improve the therapeutic benefit of anti-PD-L1 antibodies.