α1-Antichymotrypsin Present in Therapeutic C1-Inhibitor Products Competes with Selectin-Sialyl LewisX Interaction.

Engel, Ruchira; Delvasto-Nuñez, Laura; Roem, Dorina; van Mierlo, Gerard; Holst, Stephanie; Hipgrave Ederveen, Agnes L; van Buul, Jaap D; Wuhrer, Manfred; Wouters, Diana; Zeerleder, Sacha Sergio (2018). α1-Antichymotrypsin Present in Therapeutic C1-Inhibitor Products Competes with Selectin-Sialyl LewisX Interaction. Thrombosis and haemostasis, 118(12), pp. 2134-2144. Thieme 10.1055/s-0038-1675601

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BACKGROUND

C1-inhibitor (C1-inh) therapeutics can reduce neutrophil activity in various inflammatory conditions. This 'novel' anti-inflammatory effect of C1-inh is attributed to the tetrasaccharide sialyl Lewis (SLe) present on its glycans. Via SLe, C1-inh is suggested to interact with selectins on inflamed endothelium and prevent neutrophil rolling. However, C1-inh products contain plasma glycoprotein α1-antichymotrypsin (ACT) as a co-purified protein impurity.

OBJECTIVE

This article investigates the contribution of ACT to the effects observed with C1-inh.

MATERIALS AND METHODS

We have separated C1-inh and ACT from a therapeutic C1-inh preparation and investigated the influence of these proteins on SLe-selectin interactions in a specific in vitro model, which makes use of rolling of SLe-coated beads on immobilized E-selectin.

RESULTS

We find that ACT and not C1-inh, shows a clear sialic acid-dependent interference in SLe-selectin interactions, at concentrations present in C1-inh therapeutics. Furthermore, we do not find any evidence of SLe on C1-inh using either Western blotting with anti-SLe antibodies (CSLEX1 and KM93) or by mass spectrometric analysis of glycans. C1-inh reacts weakly to antibody HECA-452, which detects a broad range of selectin ligands, but ACT gives a much stronger signal, suggesting the presence of a selectin ligand on ACT.

CONCLUSION

The 'novel' anti-inflammatory effects of C1-inh are unlikely due to SLe on C1-inh and can in fact be due to SLe-like glycans on ACT, present in C1-inh products. In view of our results, it is important to assess the role of ACT in vivo and revisit past studies performed with commercial C1-inh.

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