Serum Albumin fused Flt3L expands a tolDC compartment and amplifies tolerogenic antigen immunotherapy for the prevention of pathogenic anti-drug antibody responses

Abstract From antibodies to enzyme replacement therapies, biologics and protein drugs have become a major part of the medical market revolutionized medicine. Repeated administration many these drugs, however, leads humoral responses potentially drug failure via neutralization, clearance, or immune related infusion reactions. Once pathogenic anti-drug are formed, patients must take broad immunosuppressive undergo continuous B cell depletion, discontinue treatment entirely. Currently, no approved by FDA prevent induction antibodies. Herein, we characterize effect our engineered cytokine, Flt3L-SA, in vivoand demonstrate how molecule expands dendritic cells while enhancing tolerogenic, TGFβ expressing subpopulation. We then leverage attenuate antibody response highly immunogenic Rasburicase ultimately reduce 100-fold when administered as tolerogenic regime with low dose Rasburicase. also show this reduction results fewer less severe reactions upon final challenge, evidencing both well pathology. Future work will aim determine exact mechanism which tolerance is achieved efficacy context wide range extremely including therapeutics for lysosomal storage disorders AAV therapies. Supported Chicago Immunoengineering Innovation Center Alper Family Foundation