Abstract: SA-PO722
Moss-Produced Human Factor H (CPV-104): Pioneering Rebalancing Therapies for Kidney Complement Disorders
Session Information
- Glomerular Diseases: Therapeutic Strategies
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Tschongov, Todor Alexandrov, Universitatsklinikum Freiburg Abteilung Innere Medizin IV Nephrologie und Allgemeinmedizin, Freiburg, Baden-Württemberg, Germany
- Konwar, Swagata, Universitatsklinikum Freiburg Abteilung Innere Medizin IV Nephrologie und Allgemeinmedizin, Freiburg, Baden-Württemberg, Germany
- Dabrowska-Schlepp, Paulina, Eleva GmbH, Freiburg, Baden-Württemberg, Germany
- Busch, Andreas, Eleva GmbH, Freiburg, Baden-Württemberg, Germany
- Schaaf, Andreas, Eleva GmbH, Freiburg, Baden-Württemberg, Germany
- Häffner, Karsten, Universitatsklinikum Freiburg Abteilung Innere Medizin IV Nephrologie und Allgemeinmedizin, Freiburg, Baden-Württemberg, Germany
Background
Dysregulation of the complement system can lead to various pathological conditions, particularly in the kidneys. Beside aHUS and C3G, other renal diseases are often associated with unbalanced complement activation. Drugs targeting the complement system often aim to inhibit either specific components or the entire cascade. Utilizing factor H (FH), a natural regulator of the alternative pathway, offers an alternative treatment option by restoring complement balance. Through a moss-based expression system, we developed a recombinant FH variant (CPV-104) with pharmacokinetics and pharmacodynamics comparable to native FH in vivo. In this study, we investigated dosing intervals and explored the feasibility of subcutaneous (s.c.) administration of CPV-104 in preclinical models.
Methods
B-cell and CD4 T-cell depletion was performed by injecting FH deficient mice with anti-CD20 antibody SA271G2 and anti-CD4 antibody GK1.5 at certain intervals, respectively. Depletion was confirmed by flow cytometry. Mice were treated intravenously (40 mg/kg) or s.c. (40 mg/kg; 200 mg/kg) with CPV-104 every 3, 4 or 5 days for a total of 3 injections. Blood samples were collected and the amount of FH and C3 quantified using ELISAs. Kidneys were harvested and stained for FH and glomerular C3 deposits. FH antibody formation was tested by incubating mouse sera on FH coated wells and detecting bound mouse IgGs.
Results
B- and CD4 T-cell depletion in mice allowed multiple injections of CPV-104 without causing antibody response. In FH-deficient mice, repeated CPV-104 injections normalized serum C3 levels and degraded kidney C3 deposits. Additionally, the feasibility of s.c. CPV-104 injections was explored. Initial results indicate that multiple s.c. injections lead to prolonged FH availability in mouse sera, resulting in sustained elevation of serum C3 levels and reduced kidney C3 deposits.
Conclusion
By optimizing dosing intervals and exploring s.c. administration, FH availability was significantly improved in conjunction with sustained reduction of glomerular C3 deposits in preclinical models. These findings provide valuable insights into the clinical translation of CPV-104 as a new therapeutic strategy for complement-mediated renal diseases, enabling physiological complement functionality.
Funding
- Commercial Support – Eleva GmbH