Abstract: TH-PO0687
Targeting CD11b+ Myeloid Cell Recruitment Therapeutically Treats Lupus Nephritis via Reductions in Soluble Urokinase Plasminogen Activator Receptor (suPAR) and C-C Motif Ligand 2 (CCL2) Levels
Session Information
- Glomerular Diseases: Immunopathogenesis and Targeted Therapeutics
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Li, Xiaobo, The University of Texas Medical Branch at Galveston Development Office, Galveston, Texas, United States
- Nguyen, Billy, Rush University, Chicago, Illinois, United States
- Ranjan, Nishant, The University of Texas Medical Branch at Galveston Development Office, Galveston, Texas, United States
- Balza Pineda, Santiago, 149 bio, Miami, Florida, United States
- Youssef, Mohamed A., The University of Texas Medical Branch at Galveston Development Office, Galveston, Texas, United States
- Knott, Brenna, The University of Texas Medical Branch at Galveston Development Office, Galveston, Texas, United States
- Wei, David Changli, The University of Texas Medical Branch at Galveston Development Office, Galveston, Texas, United States
- Lopez-Rodriguez, Darlah M., 149 bio, Miami, Florida, United States
- Wadhwani, Shikha, Rush University, Chicago, Illinois, United States
- Hayek, Salim, The University of Texas Medical Branch at Galveston Development Office, Galveston, Texas, United States
- Vazquez-Padron, Roberto I., University of Miami, Coral Gables, Florida, United States
- Faridi, Hafeez, Chicago State University, Chicago, Illinois, United States
- Reiser, Jochen, The University of Texas Medical Branch at Galveston Development Office, Galveston, Texas, United States
- Niewold, Timothy B., Hospital for Special Surgery, New York, New York, United States
- Gupta, Vineet, The University of Texas Medical Branch at Galveston Development Office, Galveston, Texas, United States
Background
Lupus nephritis (LN), a severe complication of systemic lupus erythematosus, is marked by immune complex deposition and immune cell infiltration in the kidney. Targeting B- and T-cells is highly effective in many, but not all, LN patients, suggesting targeting innate immune cells may improve efficacy and outcomes. CD11b is a key myeloid integrin that modulates cell adhesion and tissue recruitment. Here, we hypothesized that targeting myeloid cell activation and kidney recruitment via CD11b could reduce systemic inflammation and their kidney infiltration and ameliorate LN.
Methods
We analyzed human LN kidney scRNAseq data to identify and define the levels of CD11b+ cells. Using a first-in-class CD11b-targeting small molecule (ONT01) in four different murine models, including a humanized model, we examined efficacy of targeting myeloid cell recruitment in LN. We used a novel, transgenic mouse expressing gain-of-function mutation in CD11b to mimic the pharmacologic and define molecular mechanism.
Results
CD11b+ myeloid cells were significantly enriched in LN kidneys and were associated with disease severity and lack of treatment response. CD11b activation significantly reduced myeloid cell activation and kidney influx, glomerular injury, and proteinuria in LN models and provided therapeutic benefits even when administered after disease onset. Mechanistically, CD11b activation suppressed NF-kB and IRF3/7 signaling, reducing suPAR and CCL2 and affecting cell recruitment and influx.
Conclusion
Our study establishes that increased influx of CD11b+ myeloid cells drives LN and is associated with poorer outcomes, suggesting reducing CD11b+ cell influx as a treatment strategy. To investigate this, we used a novel CD11b agonist ONT01 (targeting CD11b+ myeloid cells) and found that it reduces kidney recruitment of these cells and decreases proteinuria. This suggests that CD11b activation could be an innovative therapeutic mechanism for LN and other autoimmune diseases. A new clinical trial has recently been launched to evaluate the therapeutic impact of this mechanism.
Funding
- NIDDK Support