Development Of A Dual-functional Conjugate Of Antigenic Peptide And Fc-? Mimetics(DCAF) For Targeted Antibody Blocking

Targeted therapy is to design therapeutic drug for specific target molecule,thereby enable enlargement of the therapeutic window by offering increased efficacy and decreased toxicity.Over recent years,with the in-depth study of the pathogenesis of diseases,molecular targeted drug have developed rapidly,mainly including small molecules and engineered antibodies that can against specific cell markers.Antibody have many positive functions,such as neutralizing pathogens,modulating the cytotoxic effects of effector cell(e.g.,phagocytes) or activating the complement cascade.However,some antibodies may also exhibit negative effects,such as crossreactive antibodies in the antibody-dependent enhancement process and over-reactive antibodies in autoimmune diseases(e.g.,myasthenia gravis) can cause damage to its own tissue.There is currently no clinically effective method for the removal of harmful antibodies,and targeted therapy can provide a clear idea for harmful antibody clearance.In the present study,we designed and synthesized a novel peptide for targeted blocking of antibodies,denoted as a dual-functional conjugate of antigenic peptide and Fc-? mimetics(DCAF).The DCAF molecule consists of three parts: an antigenic peptide that targets the variable region of the IgG,the Fc-? mimetics that binds to the Fc region of the IgG and a long alpha helix that conjugates the two peptides.We have synthesized 4 DCAF molecules and demonstrated that DCAF binds the cognate antibody with high selectivity by simultaneously binding to the Fab and Fc regions of IgG.Further experiments revealed that DCAF1 molecule can diminish the antibody-dependent enhancement effect in the dengue virus infection cell model,and DCAF4 molecule can rescue the acetylcholine receptor by inhibiting the complement cascade in the myasthenia gravis rat model.In summary,we first designed DCAF molecule that can effectively targeted block antibody function in vitro and in vivo.The development of targeted antibody blocking not only expands our knowledge about the relevance of different binding sites on IgGs,but also allows the chemical diversity to be explored in order to develop new approaches for antibody-induced disease intervention.