Specific targeting of antigen-presenting cells for immunotherapy

Abstract: Immunotherapy, which involves strategies to activate, enhance or redirect immune responses to achieve long-lasting immunity, has the potential to play an important role in the treatment of a variety of diseases. This thesis, based on four original papers, highlights different approaches to modulate immune responses by specific targeting of antigen-presenting cells. The first two studies focuses on regulation of allergic responses. In Paper I, we showed that biodegradable poly(γ-glutamic acid) (γ-PGA) nanoparticles influence allergen-specific T cell activation, suggesting a beneficial role as adjuvants in allergen-specific immunotherapy. In Paper II, the histamine H4 receptor was shown to mediate histamine-induced activation of human dendritic cells and enhance their Th2 cell stimulating capacity in response to allergen. This suggests that blocking of the histamine H4 receptor may be a promising strategy to modulate allergic responses. The last two studies involve strategies to optimise CD40-targeted cancer immunotherapy. In Paper III, adsorption of agonistic anti-CD40 monoclonal antibodies to γ-PGA nanoparticles was shown to enhance their efficacy and reduce the systemic release of cytokines after local drug delivery. In Paper IV, we demonstrated that increasing the affinity and the isoelectric point of an anti-CD40 antibody resulted in enhanced potency and tumour retention of the locally applied drug. The above strategies may thus serve to improve the efficacy and safety of local CD40-targeted immunotherapy. In conclusion, this thesis underlines the promise of directing immunotherapies to antigen-presenting cells, and in particular dendritic cells, which are central decision makers of the immune system.