Abstract
Pegylation of biopharmaceuticals is the most common strategy to increase their half-life in the blood and is associated with a reduced immunogenicity. As antigen presentation is a primary event in the activation of CD4 T-cells and initiation of Anti-Drug Antibody (ADA) response, we investigated the role of the PEG molecule on the T-cell reactivity of certolizumab pegol (CZP), a pegylated anti-TNFα Fab. We generated T-cell lines raised against CZP and its non-pegylated form (CZNP) and demonstrated CZP primed few T-cells in comparison to CZNP. CZP-primed lines from 3 donors responded to a total of 5 epitopes, while CZNP-primed lines from 3 donors responded to a total of 7 epitopes, 4 epitopes were recognized by both CZP- and CZNP-primed lines. In line with this difference of T-cell reactivity, CZP is less internalized by the dendritic cells than CZNP. In vitro digestion assay of CZP by Cathepsin B showed a rapid removal of the PEG moiety, suggesting a limited influence of PEG on CZP proteolysis. We therefore demonstrate that pegylation diminishes antigen capture by dendritic cells, peptide presentation to T-cells and T-cell priming. This mechanism might reduce immunogenicity and contribute to the long half-life of CZP and possibly of other pegylated molecules.
Highlights
Introduction of biopharmaceuticals (BP) brought clear clinical benefits for patients suffering from chronic inflammatory diseases such as rheumatoid arthritis or Crohn’s disease [1]
We showed in this study that Certolizumab pegol (CZP) induced fewer T-cells than the non-pegylated form CZP and its non-pegylated form (CZNP), shared multiple epitopes with CZNP and was less captured by dendritic cells (DCs) than CZNP
In line with the frequency of pre-existing T cells, adalimumab is known to be immunogenic in approximately one third of rheumatoid arthritis patients [11]
Summary
Introduction of biopharmaceuticals (BP) brought clear clinical benefits for patients suffering from chronic inflammatory diseases such as rheumatoid arthritis or Crohn’s disease [1]. These BPs target multiple molecules such as TNFa, IL-6R, CD20 and CD80/86, TNFa antagonists being most frequently used in the clinic. T-Cell Response to Certolizumab Pegol hinge region, the two branches being of about 20kDa [2] This large PEG moiety limits the glomerular filtration of CZP and increase its half-life in the blood, which is close to that of a full-length antibody [2]. The lack of Fc prevents binding of CZP to FcRn and transfer of CZP across the materno-foetal barrier [4, 5]
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