Karraktärisering av en AffiMab mot inflammatoriska cytokiner
Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesisAlternative title
In vitro characterization of an AffiMab that targets inflammatory cytokines (English)
The pro-inflammatory cytokine tumor necrosis factor (TNF) has long been associated with the pathogenesis of several inflammatory and autoimmune disorders, prompting the development of TNF inhibitors. Although these ihibitors have greatly revolutionized the treatment of such diseases, a subset of patients fails to respond to anti-TNF treatment. With the discovery of other central proinflammatory cytokines also implicated in the pathogenesis of inflammatory and autoimmune disorders, several inhibitors have been developed and tested in clinical trials with promising results. In the present study, the inhibitory potential of two antibody-Affibody fusion proteins (AffiMabs) targeting TNF and a second cytokine were examined. The two bispecific AffiMabs; consisting of adalimumab (an anti-TNF antibody) with two Affibody molecules fused C-terminally on either the heavy or light chain have been analyzed within the scope of this thesis. The analyzes of the AffiMabs were performed in a normal human dermal fibroblast assay using TNF and/or the second cytokine as stimuli and secretion of two different interleukins was used as readout. The analyses reveal that the AffiMabs are equally potent to adalimumab with regards to TNF inhibition, and have excellent inhibitory properties of the second cytokine. The profound inhibitory capacity of the AffiMabs can be attributed to the bivalent nature of these compounds. In addition, of the two AffiMabs examined, fusion of the Affibody to the C terminus of the light chain of adalimumab showed stronger binding to the second cytokine, while fusion of the Affibody molecule to the C terminus of heavy chain of adalimumab indicated an increased binding to the neonatal Fc receptor (FcRn) at physolological pH. These promising results make the bispecific AffiMabs studied here attractive to use in therapy for a range of indications within inflammatory and autoimmune disorders, as they inhibit the otherwise synergistic interactions between these two cytokines.
Place, publisher, year, edition, pages
Bispecific antibodies, inflammation disorders, Affibody molecules, AffiMabs
Engineering and Technology
IdentifiersURN: urn:nbn:se:kth:diva-163691OAI: oai:DiVA.org:kth-163691DiVA: diva2:801899