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

Abstract

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