Biased anti-idiotype response in rabbits leads to high-affinity monoclonal antibodies to biologics
Christina Großerichter-Wagener,
Dorien Kos,
Astrid van Leeuwen,
Lisanne Dijk,
Jorn Jeremiasse,
Floris C. Loeff,
Theo Rispens
Affiliations
Christina Großerichter-Wagener
Department of Immunopathology, Sanquin Research, Amsterdam, the Netherlands, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
Dorien Kos
Sanquin Reagents B.V., Amsterdam, The Netherlands
Astrid van Leeuwen
Biologics Laboratory, Sanquin Diagnostic Services, Amsterdam, The Netherlands
Lisanne Dijk
Department of Immunopathology, Sanquin Research, Amsterdam, the Netherlands, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
Jorn Jeremiasse
Department of Immunopathology, Sanquin Research, Amsterdam, the Netherlands, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
Floris C. Loeff
Department of Immunopathology, Sanquin Research, Amsterdam, the Netherlands, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
Theo Rispens
Department of Immunopathology, Sanquin Research, Amsterdam, the Netherlands, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
Antibody formation to human(ized) therapeutic antibodies in humans is highly skewed toward anti-idiotype responses, probably because the idiotype is the only ‘foreign’ part of the antibody molecule. Here, we analyzed antibody responses to F(ab’)2 fragments of a panel of 17 human(ized) therapeutic antibodies in rabbits. Homology between the rabbit germline and the human(ized) antibodies is moderate not only for the variable domains (both the complementarity-determining regions and the framework regions), but also for the constant domains (66% or less). Nevertheless, we observed a highly skewed anti-idiotype response in all cases, with up to >90% of the antibodies directed toward the idiotype. These results indicate that the idiotype may be inherently immunodominant. We used these biased responses to raise monoclonal rabbit anti-idiotype antibodies against secukinumab, ustekinumab, reslizumab, mepolizumab, palivizumab, and dupilumab and demonstrate the potential to develop sensitive pharmacokinetic assays with these antibodies.
