Immunological aspects of antibody formation against recombinant human therapeutics

253 Pages·2010·5.68 MB·English

Immunological aspects of
antibody formation against
recombinant human
therapeutics
The printing of this thesis was financially supported by:

Utrecht Institute for Pharmaceutical Sciences

Merck Sharp & Dohme

BD Biosciences

ISBN: 978-90-39354506

© 2010 M Sauerborn, Utrecht

Cover: Drawing inspired by the story of ‘Pied Piper of Hamelin’.
Many thanks to Soledad Ordonez Alvarez for investing time to draw the cover
and the funny cartoon on page 211 of the thesis.

Printed by: R+H Druckservice
Immunological aspects of antibody formation against
recombinant human therapeutics

Immunologische aspecten van antilichaam productie tegen recombinant
humane therapeutische eiwitten

(met een samenvatting in het Nederlands)

Proefschrift

ter verkrijging van de graad van doctor aan de Universiteit Utrecht
op gezag van de rector magnificus, prof.dr. J.C. Stoof,
ingevolge het besluit van het college voor promoties
in het openbaar te verdedigen op maandag 6 december 2010
des middags te 2.30 uur

door

Melody Sauerborn

geboren op 28 november 1980 te Krefeld, Duitsland
Promotoren: Prof.dr. H. Schellekens
Prof.dr. W. Jiskoot
Do not worry about your difficulties in Immunogenicity.
I can assure you mine are still greater.
- Melody Sauerborn, adapted from Albert Einstein,

Table of Contents Page

Part I
…the weird (recombinant human therapeutics), the bad (anti-drug antibodies)
and the good (mouse models)!

Chapter 1 11
Immunological mechanism underlying the immune response to
recombinant human protein therapeutics

Chapter 2 33
Aggregated recombinant human interferon beta induces antibodies
but no memory in immune tolerant transgenic mice

Chapter 3 65
Immunological mechanism of antibody induction by human interferon
beta aggregates in an immune tolerant mouse model

Chapter 4 95
Immunological aspects of the formation of anti-drug antibodies against
aggregated recombinant human alpha in an immune tolerant mouse model

Chapter 5 133
Marginal zone B cells influence magnitude of antibody response against
Betaferon® in immune tolerant mice

Part II
Natural antibodies and their influence on immunogenicity

Chapter 6 151
B-1 cells and naturally occurring antibodies: Influencing the immunogenicity
of recombinant human therapeutic proteins?
Page

Chapter 7 171
Natural antibodies against bone morphogenic proteins and interferons in
healthy donors and patients with infections linked to type-1 cytokine responses

Chapter 8 193
Summary, general discussion and future perspectives

Appendices 213
Affiliations of collaborating authors
List of abbreviations
Glossary
Curriculum Vitae
List of publications
Nederlandse Samenvatting
Deutsche Zusammenfassung
Acknowledgments
Part
…the weird (recombinant human
therapeutics),
the bad (anti-drug antibodies),
and the good (mouse models)!