Background: Proliferative lupus nephritis (LN) involves immune complex deposition in the kidney that can severely impact normal renal clearance mechanisms. Immune complexes can activate C1q and the classical complement cascade, and along with pathogenic anti-C1q antibodies (PACAs), may amplify inflammation and disease progression. Martin et al reported that circulating C4d, a marker of complement activation downstream of the C1 complex, correlated well with C4d immunohistochemistry score in kidney tissue and could be a sensitive and specific biomarker for diagnosing active LN. ¹

Objectives: To confirm and extend observations by Martin et al, and to extend a link between C4d, C1q activation, and PACA levels to identify patients most likely to have the classical complement pathway as a driving component of disease. Such patients would be potential candidates for anti-C1q therapy, such as ANX009, to dampen disease activity and slow disease progression (NCT04535752).

Methods: Plasma samples were collected from a cohort of 40 LN patients (20 with disease flare and 20 without disease flare) from the California Lupus Epidemiology Study (CLUES), a multi-racial/ethnic cohort of individuals with physician-confirmed systemic lupus erythematosus, and 20 healthy controls ( Table 1 ). A panel of complement factors, including 15 complement protein and relevant complexes, were measured using an enzyme-linked immunosorbent assay. Clinical disease activity was measured using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and proteinuria was evaluated by a random spot urine protein to creatinine ratio (UPCR).

Results: We observed evidence of coordinated complement activation in LN patients relative to healthy controls. Specifically, levels of C4d and the C4d/C4 ratio were highly increased in LN patients with flare, while levels of C1q, C1s, and C4 were decreased, consistent with activation of the classical complement pathway (increased activation and component consumption). The C4d/C4 ratio also correlated with levels of PACA isotypes 1 and 3 that are known to activate the classical pathway. Improvements in C4 and C4d/C4 ratio were associated with improvements in proteinuria and SLEDAI following treatment for disease flare, indicating their potential value as biomarkers of treatment response.

Conclusion: A subset of LN patients exhibited high C4d/C4 ratio along with specific markers of classical pathway activation, indicating that the classical complement pathway may be a driving component of their disease. Reduction in this ratio appears to correlate with treatment response, but its levels are generally not normalized, suggesting an insufficient resolution of complement-mediated inflammation by currently available treatments. Our data support a clinical hypothesis that a subset of LN patients may benefit from a precision medicine approach targeting the classical complement pathway ( Figure 1 ). This hypothesis will be evaluated in a forthcoming clinical trial testing the subcutaneously administered C1q inhibitor ANX009 in patients with active LN.

REFERENCES:

[1]Martin M, Trattner R, Nilsson SC, et al. Plasma C4d Correlates With C4d Deposition in Kidneys and With Treatment Response in Lupus Nephritis Patients. Front Immunol . 2020;11:582737.

Acknowledgements: Supported by: Annexon Biosciences

Disclosure of Interests: Ann Mongan Employee of: Annexon Biosciences, Poojan Suri Employee of: Annexon Biosciences, Maze Therapeutics, Dean Richard Artis Shareholder of: Annexon Biosciences, Bristol Myer Squibb, Roche, Sanofi, BMS, J&J, Employee of: Annexon Biosciences, Ellen Cahir-McFarland Shareholder of: Annexon Biosciences, Employee of: Annexon Biosciences, Biogen, Henk-André Kroon Shareholder of: Annexon Biosciences, Employee of: Annexon Biosciences, Yaisa Andrews-Zwilling Employee of: Annexon Biosciences, Shawn Rose Employee of: Annexon, Johnson & Johnson, Sanjay Keswani Shareholder of: Annexon Biosciences, Nura Bio, Employee of: Annexon Biosciences, Nura Bio, Maria Dall’Era Consultant of: GSK, AstraZeneca, Biogen, Annexon Biosciences, Pfizer, Aurinia, Grant/research support from: Annexon Biosciences, GSK, Ted Yednock Shareholder of: Annexon Biosciences, Consultant of: Cortexyme, Employee of: Annexon Biosciences