Tissue-specific complement inhibition by antibody-Complement Regulatory Protein (CRP) fusions utilizing Therapeutic Autoimmune reguLatOry proteiN (TALON™) platform

Abstract

Abstract The complement system plays a major role in humoral innate immunity. Upon activation, complement proteins trigger a cascade of enzymatic events leading to the production of inflammatory mediators and membrane attack complexes. Tight regulation of complement proteins is essential for immune homeostasis due to their potency and abundance in fluid phase. Complement Regulatory Proteins (CRPs) that are membrane-bound (e.g., CD59), or in fluid phase (e.g., Factor H), prevent aberrant activation of complement pathways against self and mitigate autoimmunity. The importance of CRPs is underscored by the finding that genetic variations in the CRPs can lead to autoimmune diseases such as paroxysmal nocturnal hemoglobinuria (PNH) characterized by the lysis of host red blood cells from dysregulated complement system. Systemic complement inhibition via anti-C5 antibody has clinically been shown to benefit some patients with complement-mediated disorders, but the therapy requires a high, frequent dosing scheme and supplemental vaccinations to compensate for systemic immunosuppression. In addition, other diseases such as C3 glomerulopathy affect specific tissues and involve pathways beyond C5, limiting treatment options. To this end, local immunomodulation through targeted delivery of CRPs to specific tissues is an attractive strategy to restore homeostasis in complement-mediated autoimmune diseases while circumventing the need for high dose systemic inhibition of complement factors. Here, we present a proof-of-concept study for the design, generation, and evaluation of tissue-tethering antibodies fused with CRPs. Also, we demonstrate the pharmacokinetics and pharmacodynamics of tissue-targeting CRP fusions in mouse models.