Kidney Week

Abstract: FR-OR081

Investigating the Role of CD40-CD154 Interactions in Lupus Nephritis

Session Information

• Lupus and Then Some
  November 08, 2019 | Location: Ballroom C, Walter E. Washington Convention Center
  Abstract Time: 04:30 PM - 04:42 PM

Category: Glomerular Diseases

• 1202 Glomerular Diseases: Immunology and Inflammation

Authors

• Rush, James, Novartis Institutes for Biomedical Research, Basel, Switzerland

James Rush, PhD

James Rush is the Head of the Translational Research group in the Autoimmunity, Transplantation and Inflammation disease area at the Novartis Institutes for Biomedical Research in Basel. James received his Bachelors in Applied Science (Hons) from the University of Western Sydney in 1994 and Ph.D. from Sydney University in 2000. He completed a HHMI postdoctoral fellowship at Yale University in the laboratories of David Schatz and Charlie Janeway. After his postdoctoral work, he joined the Genomics Institute of the Novartis Research Foundation in San Diego in May 2005 where his lab utilized high throughput genomics and small molecule screening technologies to identify novel regulators of innate immune receptor and B cell function. He then moved to NIBR in 2008 to lead a project team working on the development of a novel immunomodulatory antibody targeting the CD40 receptor that has achieved positive clinical proof-of-concept in kidney transplantation and Sjögren’s syndrome. Additionally, his group focuses on the profiling and analyses of human disease samples to enable development of therapeutics targeting dysregulated immunity in autoimmune disease, chronic kidney diseases and solid organ transplantation. Areas of focus include application of multi-omics profiling and analyses to understand disease biology and inform clinical development, as well as helping facilitate the professional development of his co-workers. More recently, he has developed a strong interest in how real-world evidence and reimbursement-relevant outcomes are used in clinical development.

• Nuesslein-Hildesheim, Barbara, Novartis Institutes for Biomedical Research, Basel, Switzerland

Barbara Nuesslein-Hildesheim,

• Lafossas, Frédérique, Novartis Institutes for Biomedical Research, Basel, Switzerland

Frédérique Lafossas,

• Wieczorek, Grazyna, Novartis Institutes for Biomedical Research, Basel, Switzerland

Grazyna Wieczorek,

• Ceci, Melanie, Novartis Institutes for Biomedical Research, Basel, Switzerland

Melanie Ceci,

• Gaulis, Swann, Novartis Institutes for Biomedical Research, Basel, Switzerland

Swann Gaulis,

• Palla, Giovanni, Novartis Institute for BioMedical Research, Basel, Switzerland

Giovanni Palla,

• Mcmichael, Katriona, Novartis Institutes for Biomedical Research, Basel, Switzerland

Katriona Mcmichael,

• Ferrero, Enrico, Novartis Institutes for Biomedical Research, Basel, Switzerland

Enrico Ferrero,

• Pfister, Sabina, Novartis Pharma AG, Basel, Switzerland

Sabina Pfister,

Background

Disease pathology in lupus nephritis (LN) has been linked to a variety of different immune pathways, including CD40-CD154 interactions. This pathway has been shown to regulate the activation of B lymphocytes as well as macrophages and activated renal epithelia, and thus blockade of this pathway could provide therapeutic benefit in individuals with LN.

Methods

We evaluted the expression and activation of the CD40-CD154 pathway in kidney tissue from LN patients. Additionally, we evaluted the therapeutic effect of a blocking, non-depleting anti-mouse CD40 mAb (GOT40) in the NZB/W F1 model of lupus nephritis.

Results

Histological analysis of kidney biopsies from patients with proliferative LN revealed evidence of CD40 and CD154 on B cells, macrophages and T cells respectively. These results suggested that there might be ongoing T-B cell collaboration in LN kidneys and we subsequently examined whether there was evidence of CD40 pathway expression and activation in situ. Using published scRNA-seq data from LN kidney biopsies we could demonstrate evidence of CD40 transcript expression by B cells and myeloid cells and CD154 expression by subsets of CD4+ T cells. To directly address the role of CD40-CD154 in LN, we used GOT40, a novel, blocking, non-depleting anti-CD40 antibody in the NZB/W F1 model of lupus nephritis. Therapeutic treatment for 9-77 days of NZB/W F1 mice aged 24 to 37 weeks and individually enrolled into treatment groups with proteinuria ≥3 mg/ml resulted in suppression of established proteinuria and extended survival in GOT40 treated animals in comparison to isotype control treated animals. Serum autoantibody and CXCL13 levels were reduced by GOT40 treatment compared to isotype control. Similar to current treatments, we observed only minimal (not significant) reduction in various histological parameters with GOT40 treatment at this advanced stage of kidney injury, despite evidence of complete, systemic pathway blockade at the transcriptional level and suppression of a kidney gene expression with GOT40 treated animals.

Conclusion

Our data support the notion that CD40-CD154 pathway signaling may contribute to pathology in LN and that anti-CD40 treatment could provide therapeutic benefit in individuals suffering from this disease.

Funding

• Commercial Support –