Monoclonal antibodies and other biologic agents in the treatment of asthma

Abstract

Asthma represents a syndrome of airway inflammatory diseases with complex pathology. The immunologic pathogenesis is being increasingly revealed and provides opportunity for targeted biological intervention. Current experience with immunomodulators as targeted therapy in asthma is described in this literature review. Targeted therapies have included strategies to activate dendritic cells through the TLR-9 receptors, to interrupt the action of T(H)2 cytokines with cytokine blockers and monoclonal antibodies, to promote development of T(H)1 responses, to block IgE mediated pathways and to block TNFalpha. Omalizumab is the only biological therapy that has an approved indication in asthma at this time. An improved understanding of the heterogeneity of asthma should allow for specific targeting of different disease phenotypes specific therapies including immunomodulators.

Figure 1

Schematic depiction of the components of the airway allergic inflammatory response. PRR (pattern recognition receptor); PAR (protease activated receptor); TSLP (thymic Stromal Lymophopoietin); GM-CSF (granulocyte-macrophage colony stimulating factor). Arrows indicate the direction in which the identified signal is acting. Red lines indicate the discharge of cellular mediators (including granular contents, lipid mediators and cytokines).

Figure 2

(A) TLR 9 agonists act on dendritic cells in conjunction with antigen and result in a preferential activation of antigen specific T_H12 cells (green line) and inhibition of development of antigen specific T_H2 cells (red X). (B) Anti IL-4 agents block the development of T_H2 cells, whether the source of the IL-4 is from activated basophils or eosinophils or from the stimulated T_H0 cells. This in turn has the potential to diminish production of all T_H2 products-indicated by broken red circle surrounding the T_H2 cell. (C) Anti IL-5 agents block the development and release from the bone marrow of eosinophils. This has the potential to result in less tissue eosinophilia in allergic inflammation and less exposure to mediators from activated eosinophils-indicated by broken red circle surrounding the eosinophil. (D) IL-9 is a product of activated T_H2 cells which can directly activate mast cells. Anti IL-9 could inhibit this. (E) IL-13 is a product of activated Th2 cells with activities in determining isotype switch to IgE of allergen specific B cells, direct activation mast cells and effects on airway goblet cell activity and mucus production. Anti IL-13 has the potential to inhibit these various activities. (F) Anti-IgE results in loss of high-affinity IgE receptors of mast cell and basophils with result diminished capacity for activation after allergen exposure. Anti-IgE reduces high affinity IgE receptors on dendritic cells which may in turn decrease allergen processing and presentation.