Kidney Week

Abstract: FR-OR34

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

Session Information

• Glomerular Diseases: Antibodies, Complement, and Inflammatory Mediators
  November 05, 2021 | Location: Simulive, Virtual Only
  Abstract Time: 04:30 PM - 06:00 PM

Category: Glomerular Diseases

• 1202 Glomerular Diseases: Immunology and Inflammation

Authors

• Wawersik, Stefan, Q32 Bio, Cambridge, Massachusetts, United States

Stefan Wawersik, PhD

• Liu, Fei, Q32 Bio, Cambridge, Massachusetts, United States

Fei Liu,

• Ryan, Sarah T., Q32 Bio, Cambridge, Massachusetts, United States

Sarah T. Ryan,

• Fahnoe, Kelly C., Q32 Bio, Cambridge, Massachusetts, United States

Kelly C. Fahnoe,

• Morgan, Jennifer, Q32 Bio, Cambridge, Massachusetts, United States

Jennifer Morgan,

• Salant, David J., Boston University Medical Center, Boston, Massachusetts, United States

David J. Salant,

• Thurman, Joshua M., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Joshua M. Thurman,

• Kalled, Susan, Q32 Bio, Cambridge, Massachusetts, United States

Susan Kalled,

• Violette, Shelia, Q32 Bio, Cambridge, Massachusetts, United States

Shelia Violette,

Background

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.

Methods

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 (fH_1-5). 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.

Results

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 fH_1-5 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.

Conclusion

These data provide proof-of-concept that targeting fH_1-5 to deposited C3d results in potent, durable, and efficacious complement blockade in kidney while avoiding systemic complement inhibition.

Funding

• Commercial Support – Q32 Bio