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Abstract: FR-OR34

C3d-Targeted Factor H Achieves Potent Renal Complement Inhibition and Reduced Glomerular Injury Without Affecting Systemic Complement

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation


  • Wawersik, Stefan, Q32 Bio, Cambridge, Massachusetts, United States
  • Liu, Fei, Q32 Bio, Cambridge, Massachusetts, United States
  • Ryan, Sarah T., Q32 Bio, Cambridge, Massachusetts, United States
  • Fahnoe, Kelly C., Q32 Bio, Cambridge, Massachusetts, United States
  • Morgan, Jennifer, Q32 Bio, Cambridge, Massachusetts, United States
  • Salant, David J., Boston University Medical Center, Boston, Massachusetts, United States
  • Thurman, Joshua M., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Kalled, Susan, Q32 Bio, Cambridge, Massachusetts, United States
  • Violette, Shelia, Q32 Bio, Cambridge, Massachusetts, United States

Complement is critical to both the innate and adaptive immune systems, serving an essential role in pathogen response and as an effector of humoral immunity. This system is tightly controlled, and inappropriate activation can cause inflammation and organ injury. Consequently, inhibition has been pursued as a therapeutic strategy for rare complement-driven diseases. However, complement proteins exist in high abundance systemically and undergo rapid turnover, making effective chronic inhibition challenging. Furthermore, because of the complement system’s essential role in immunity, systemic blockade raises the risk of infection in patients. As a result, substantial unmet need remains for safer and more effective anti-complement therapies, particularly for chronic diseases.


We designed a targeted fusion protein to inhibit complement activation in tissue while minimizing systemic blockade. ADX-097 is a humanized anti-C3d monoclonal antibody linked to five N-terminal consensus repeats of the complement inhibitor factor H (fH1-5). We evaluated tissue targeting and both circulating and tissue PK and PD of a mouse ADX-097 surrogate, ADX-118, in fH-/- mice, which exhibit robust glomerular complement activation. We also examined disease-modifying efficacy of ADX-097 in the rat Passive Heymann Nephritis (PHN) model of membranous nephropathy.


We demonstrate that our anti-C3d antibody binds high-density glomerular C3d deposits across a range of renal diseases, indicating that this binding could deliver fH1-5 locally. In fH-/-mice, a single subcutaneous dose of 1 mg/kg ADX-118 achieves >75% complement inhibition in glomeruli for at least 7 days post-dose while avoiding systemic complement blockade. A lower, 0.3 mg/kg dose achieves approximately 50% inhibition in glomeruli. In the rat PHN model, a single 1 mg/kg dose of ADX-097 inhibits glomerular complement and significantly reduces urine protein- and albumin-creatinine ratios, indicating potent disease-modifying efficacy.


These data provide proof-of-concept that targeting fH1-5 to deposited C3d results in potent, durable, and efficacious complement blockade in kidney while avoiding systemic complement inhibition.


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