24 Jan The CD6/ALCAM Pathway Promotes Lupus Nephritis via T cell–Mediated Responses
Stephen Connelly, PhD
Co-founder & Chief Scientific Officer
San Diego, California
MedicalResearch.com: What is the background for this study?
Response: Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease that predominantly affects women in the reproductive age range. Approximately 50% of SLE patients experience lupus nephritis (LN), a serious complication that is accompanied by significant morbidity and mortality. Progression of LN to chronic kidney disease is common, with 10% of patients with LN developing end-stage kidney disease.
T cells, play a central role in the pathogenesis of both SLE and LN by mediating tissue damage and enhancing the production of autoantibodies by promoting B cell differentiation, proliferation, and maturation. These T cells express CD6, a costimulatory receptor that through its binding to activated leukocyte cell adhesion molecule (ALCAM), expressed on immune cells and tissues, modulates both the activity and trafficking of effector T cells (Teff). The expression of both CD6 and ALCAM (CD6-ALCAM pathway) have been associated with pathogenic effector T cell activity and trafficking in multiple autoimmune and inflammatory diseases.
Based on a comprehensive screen of more than 1100 urine proteins, soluble urinary ALCAM (uALCAM) was identified as one of only a few molecules that were elevated in the urine of patients with SLE with active renal involvement compared with patients with quiescent or no prior nephritis. However, no studies had been conducted to characterize the cellular sources of the soluble ALCAM and questions remained about the relevance of this protein and whether it was associated with the pathology of the disease.
MedicalResearch.com: What are the main findings?
Response: In the publication, we demonstrated the involvement of the CD6-ALCAM pathway in two ways:
- Using samples from human lupus nephritis patients, we provided robust validation showing uALCAM is a biomarker that can discern active renal involvement in SLE vs. inactive, or no renal involvement across a range of ethnicities. Notably, not only did the uALCAM level correlate with clinical measures of LN disease severity, but single cell RNA sequencing data from kidney tissues indicated an increase in CD6 expressing T cells and ALCAM on infiltrating leukocytes and resident kidney cells in LN patients, linking this pathway more closely with renal disease progression.
- To test the role of the CD6-ALCAM pathway in disease pathogenesis, we used CD6 blockade in animal models of SLE/LN. Blockade of CD6 demonstrated the pathway’s ability to prolong survival, decrease infiltrating immune cells, lower cytokine levels, and reduce renal pathology in a manner comparable to mycophenolate mofetil and cyclophosphamide, both potent immunosuppressors used in the treatment of LN. By specifically targeting CD6 on T cells, not only was there a decrease in T cell infiltration and activity but this led to decreased activity of other immune cell types, including inflammatory macrophages and neutrophils.
MedicalResearch.com: What should readers take away from your report?
Response: Pathogenic T cells are instrumental in the development and progression of both SLE and LN. Our work demonstrates that the CD6-ALCAM pathway is not only a driver of disease and an attractive therapeutic target, but further validates using ALCAM as a biomarker to monitor disease.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Key learnings and future recommendations will come from the results of our Phase 1b EQUALISE trial in lupus nephritis patients where we are studying itolizumab, our anti-CD6 monoclonal antibody. Understanding the relationship between increased urinary ALCAM and clinical responses will be highly informative as to the potential utility of this biomarker in clinical development and practice. Itolizumab has already demonstrated encouraging results in SLE patients without LN that had elevated urine protein/creatinine and albumin/creatinine ratios, where we saw a decrease in proteinuria. We’re excited to highlight interim data from this study later this year.
MedicalResearch.com: Is there anything else you would like to add?
Response: Targeting the CD6-ALCAM pathway and modulating both the activity and trafficking of T cells is highly differentiated, while the use of a targeted therapy alongside biomarker approaches is unique to Equillium. We believe itolizumab may provide a more precise treatment option for patients with a favourable safety and tolerability profile.
J Clin Invest. 2022;132(1):e147334. https://doi.org/10.1172/JCI147334.
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