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• W4283013721 abstract "IntroductionWhile systemic complement inhibition is a therapeutic strategy for complement-driven diseases, potency and durability of inhibition are limited by high circulating concentrations and rapid turnover of complement proteins. Furthermore, because of complement’s essential role in innate and adaptive immunity, systemic blockade raises infection risk in patients. Consequently, substantial unmet need remains for safer and more effective anti-complement therapies, particularly for chronic diseases. We designed ADX-097, a bi-functional fusion protein, ADX097 comprising a humanized anti-C3d monoclonal antibody linked to two moieties of the first five consensus repeats of factor H (fH1-5). ADX-097 was designed to locally inhibit complement activation in diseased tissue while minimizing systemic blockade.MethodsWe characterized circulating and tissue PK/PD of ADX-097 in a non-human primate (NHP) model of UVB induced complement activation in the skin and of ADX-118, a mouse surrogate, in factor H-/- mice, a model of glomerular complement activation. We also evaluated PK/PD and efficacy for ADX-097 in the rat Passive Heymann Nephritis (PHN) model of membranous nephropathy. We have further explored the utility of C3d targeted therapies by demonstrating C3 complement activation and C3d deposition in human renal and skin disease biopsies by immunohistochemistry.ResultsADX-097 is a humanized anti-C3d monoclonal antibody linked to five N-terminal consensus repeats of the complement AP inhibitor factor H (fH1-5). In a NHP model of skin injury, we show that ADX-097 dosed subcutaneously (SC) as low as 1 mg/kg distributes to skin where C3d is deposited and inhibits complement activation. An ADX-118 dose-response PK/PD study in factor H-/- mice showed that a single SC dose at 1 mg/kg achieves >75% glomerular complement inhibition for at least 7 days while avoiding systemic complement blockade, and a 0.3 mg/kg dose achieves approximately 50% glomerular inhibition. In a rat PHN model, ADX-097 dosed SC or IV at 1 mg/kg inhibited glomerular complement activation and significantly reduced urine protein- and albumin-creatinine ratios. Efficacy of ADX-097 at 1 mg/kg was equivalent to full systemic blockade of complement using daily injections of cobra venom factor, indicating potent disease-modifying efficacy. Furthermore, equimolar doses of a non-targeted inhibitor (Fc-fH1-5) did not similarly reduce proteinuria. Importantly, analysis of serum samples in zymosan assays indicated ADX-097 achieved this efficacy without inhibition of systemic complement activity. Collectively, this data suggests C3d-mediated tissue targeting drives ADX-097 potency and efficacy. Finally, we demonstrate C3d deposition and C3 complement activation by immunohistochemistry across several human renal, liver, and skin diseases, indicating the broad potential for C3d-targeted delivery complement negative regulatory proteins to diseased tissue.ConclusionsThese data demonstrate the therapeutic potential of ADX-097 and show that C3d-mediated tissue targeting of fH1-5 in preclinical models results in potent, durable, and efficacious local AP complement blockade without systemic complement inhibition.Conflict of interest Corporate sponsored research or other substantive relationships:Ownership & employee: Q32 BioOwnership: Scholar Rock IntroductionWhile systemic complement inhibition is a therapeutic strategy for complement-driven diseases, potency and durability of inhibition are limited by high circulating concentrations and rapid turnover of complement proteins. Furthermore, because of complement’s essential role in innate and adaptive immunity, systemic blockade raises infection risk in patients. Consequently, substantial unmet need remains for safer and more effective anti-complement therapies, particularly for chronic diseases. We designed ADX-097, a bi-functional fusion protein, ADX097 comprising a humanized anti-C3d monoclonal antibody linked to two moieties of the first five consensus repeats of factor H (fH1-5). ADX-097 was designed to locally inhibit complement activation in diseased tissue while minimizing systemic blockade." @default.
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• W4283013721 date "2022-06-01" @default.
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• W4283013721 title "POS-042 C3d-Directed Factor H Targeting Delivers Potent and Durable Complement Inhibition and Disease-Modifying Efficacy In Kidney and Skin Without Inhibiting Systemic Complement" @default.
• W4283013721 doi "https://doi.org/10.1016/j.ekir.2022.04.064" @default.
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