RT Journal Article
SR Electronic
T1 ALX-0962, an anti-IgE Nanobody® with a dual mode of action
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1765
VO 42
IS Suppl 57
A1 Manuela Rinaldi
A1 Tinneke Denayer
A1 Sophie Thiolloy
A1 Luis C. Perez Tosar
A1 Marie-Ange Buyse
A1 Philip De Decker
A1 Emilie De Witte
A1 Peter Meerts
A1 Judith Baumeister
A1 Josefin-Beate Holz
YR 2013
UL http://erj.ersjournals.com/content/42/Suppl_57/1765.abstract
AB Background The interaction of IgE with its high affinity receptor FcεRI on mast cells and basophils is essential to induce an allergic response. Omalizumab, a competitive inhibitor of circulating IgE, is used to treat allergic asthma. However, the dissociation of IgE-FcεRI complexes is very slow and this interaction is not influenced by Omalizumab. Here we describe ALX-0962, a bispecific Nanobody (Nb) (single variable domain of antibody) targeting IgE as well as human serum albumin to obtain plasma half-life extension.AimThe aim of this study was to explore the IgE-Nb complex formation and establish the mode of action (MoA) of ALX-0962.Methods The IgE-Nb complex was investigated using surface plasmon resonance (SPR) and electrochemiluminescence (ECL), while the MoA was explored with SPR and with XCELLigence using human FcεRI transfected rat basophil cells in a degranulation assay.Results SPR and ECL indicated the occurrence of 1:2 IgE-Nb complex, with at least one Nb binding site preventing the interaction with the FcεRI epitope. Next, investigation of the MoA demonstrated a dual functionality of the Nb:1) neutralization of soluble IgE with a higher potency than Omalizumab 2) binding and displacement of preformed IgE-FcεRI complexes on basophils.The displacement by ALX-0962 was verified in the cell based assay, demonstrating a significant decrease in degranulation for Nb at nM range, while no decrease was observed for Omalizumab.Conclusion Our results show that ALX-0962 has a dual mode of action: it neutralizes soluble IgE and displaces preformed IgE-FcεRI complexes as shown in vitro.This could lead to a faster onset of action compared to Omalizumab, potentially resulting in an earlier clinical improvement in asthma.