Ebribafusp alfa (ADX-097) comprising a humanized anti-C3d monoclonal antibody linked to two moieties of the first five consensus repeats of factor H (fH1-5). Ebribafusp alfa binds C3d and related fragments, catalyzes AP convertase dissociation, acts as a factor I co-factor for C3b cleavage, and delivers fH1-5 moieties to C3d -deposited tissues for local complement inhibition without systemic blockade. Ebribafusp alfa reduces glomerular C3 deposition, proteinuria, urine albumin-creatinine ratios, and urine soluble C5b-9 levels, preserves podocyte foot-process architecture, inhibits skin complement activation, and localizes to UVB-damaged primate skin. Ebribafusp alfa can be used for the research of membranous nephropathy, bullous pemphigoid, discoid lupus erythematosus, C3 glomerulopathy, IgA nephropathy, and lupus nephritis [1] [2].
In Vivo, Ebribafusp alfa (1 mg/kg; s.c., i.v.; single dose) provides potent disease-modifying efficacy in the rat PHN model of membranous nephropathy without systemic complement inhibition[1]. Ebribafusp alfa (5 mg/kg; i.v.; single dose) durably inhibits glomerular complement deposition in CfH-/- mice by localizing to complement-active glomeruli[2]. Ebribafusp alfa (1-30 mg/kg; i.v.; single dose; 0.3-3 mg/kg; s.c.; single dose) reduces proteinuria and glomerular complement deposition in rat passive Heymann nephritis, with doses ≤10 mg/kg i.v. or ≤3 mg/kg s.c. showing no systemic complement inhibition[2]. Ebribafusp alfa (1-30 mg/kg; s.c.; single dose) localizes to complement-active primate skin at doses as low as 1 mg/kg s.c., with transient systemic complement inhibition only observed at higher doses[2].
In Vitro, Ebribafusp alfa (10-4,200 RU; 120 s injection, 180 s dissociation) binds recombinant human C3d with avidity-dependent affinity, showing a >2,000-fold increase in binding strength as C3d surface density increases 420-fold from 10 RU to 4,200 RU[2]. Ebribafusp alfa (IC50 concentrations) selectively inhibits the human alternative complement pathway with high potency (IC50 = 81 nM) and exhibits ~7.5-fold weaker activity against the classical complement pathway[2]. Ebribafusp alfa (IC50 concentrations) inhibits complement activity in human, mouse, and rat serum, with highest potency in rat serum (IC50 = 99 nM) and similar potency in human and mouse serum[2]. Ebribafusp alfa retains factor I co-factor activity for fluid-phase C3b cleavage, with efficiency comparable to isolated fH1-5[2]. Ebribafusp alfa (0.056-7 μM) potently inhibits complement deposition on human skin explants exposed to bullous pemphigoid serum, with significant inhibition observed at concentrations ≥0.28 μM[2].
References:
[1]. 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.
[2]. Liu F, et al. C3d-Targeted factor H inhibits tissue complement in disease models and reduces glomerular injury without affecting circulating complement. Molecular therapy: the journal of the American Society of Gene Therapy. 2024 Apr 03;32(4):1061-1079.
In Vivo, Ebribafusp alfa (1 mg/kg; s.c., i.v.; single dose) provides potent disease-modifying efficacy in the rat PHN model of membranous nephropathy without systemic complement inhibition[1]. Ebribafusp alfa (5 mg/kg; i.v.; single dose) durably inhibits glomerular complement deposition in CfH-/- mice by localizing to complement-active glomeruli[2]. Ebribafusp alfa (1-30 mg/kg; i.v.; single dose; 0.3-3 mg/kg; s.c.; single dose) reduces proteinuria and glomerular complement deposition in rat passive Heymann nephritis, with doses ≤10 mg/kg i.v. or ≤3 mg/kg s.c. showing no systemic complement inhibition[2]. Ebribafusp alfa (1-30 mg/kg; s.c.; single dose) localizes to complement-active primate skin at doses as low as 1 mg/kg s.c., with transient systemic complement inhibition only observed at higher doses[2].
In Vitro, Ebribafusp alfa (10-4,200 RU; 120 s injection, 180 s dissociation) binds recombinant human C3d with avidity-dependent affinity, showing a >2,000-fold increase in binding strength as C3d surface density increases 420-fold from 10 RU to 4,200 RU[2]. Ebribafusp alfa (IC50 concentrations) selectively inhibits the human alternative complement pathway with high potency (IC50 = 81 nM) and exhibits ~7.5-fold weaker activity against the classical complement pathway[2]. Ebribafusp alfa (IC50 concentrations) inhibits complement activity in human, mouse, and rat serum, with highest potency in rat serum (IC50 = 99 nM) and similar potency in human and mouse serum[2]. Ebribafusp alfa retains factor I co-factor activity for fluid-phase C3b cleavage, with efficiency comparable to isolated fH1-5[2]. Ebribafusp alfa (0.056-7 μM) potently inhibits complement deposition on human skin explants exposed to bullous pemphigoid serum, with significant inhibition observed at concentrations ≥0.28 μM[2].
References:
[1]. 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.
[2]. Liu F, et al. C3d-Targeted factor H inhibits tissue complement in disease models and reduces glomerular injury without affecting circulating complement. Molecular therapy: the journal of the American Society of Gene Therapy. 2024 Apr 03;32(4):1061-1079.