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Abstract
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.
Highlights
The programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has a central role in suppression of anti-tumor immunity [1]
It was recently shown that the Fc region contributes to the efficacy of anti-PD-L1 antibodies in the way that isotypes with higher affinity to activating FcγR mediate increased anti-tumor activity [13] providing us the rationale to investigate if glyco-engineering of anti-PD-L1 antibodies might result in further improvement
Atezolizumab is a humanized IgG1 antibody which lacks the N-glycosylation site in its Fc region by changing an aspartic acid into alanine at amino acid position 298 in the heavy chain leading to minimized binding to FcγRs [23]
Summary
The programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has a central role in suppression of anti-tumor immunity [1]. PD-L1 ( known as CD274 or B7-H1), a B7 family member, is a transmembrane protein broadly expressed in hematopoietic cells, such as B and T lymphocytes and macrophages and on nonhematopoietic cells [2, 3]. PD-1, the receptor of PD-L1, is a member of the CD28 family expressed on activated T cells [4]. Engagement of PD-1 on T cells by PD-L1 leads to their functional suppression evident by decreased cytokine production and proliferation [3]. In addition to its function as a ligand for PD-1, PD-L1 can bind to CD80 resulting in inhibition of T cell activation [7]
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