Glyco-Engineered Anti-Human Programmed Death-Ligand 1 Antibody Mediates Stronger CD8 T Cell Activation Than Its Normal Glycosylated and Non-Glycosylated Counterparts.

Autor:	Goletz C; Glycotope GmbH, Berlin, Germany., Lischke T; Glycotope GmbH, Berlin, Germany., Harnack U; Glycotope GmbH, Berlin, Germany., Schiele P; Glycotope GmbH, Berlin, Germany., Danielczyk A; Glycotope GmbH, Berlin, Germany., Rühmann J; Glycotope GmbH, Berlin, Germany., Goletz S; Glycotope GmbH, Berlin, Germany.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2018 Jul 16; Vol. 9, pp. 1614. Date of Electronic Publication: 2018 Jul 16 (Print Publication: 2018).
DOI:	10.3389/fimmu.2018.01614
Abstrakt:	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 FcγRs. 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 FcγRIIIa 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 FcγRIIIa 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.
Databáze:	MEDLINE
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