GMP-Ready Smith-Specific Regulatory T Cell Therapy to Treat Lupus Nephritis

Regulatory T cells (Tregs) are a specialized type of immune cell that act as the body’s “peacekeepers,” ensuring the immune system doesn’t attack healthy tissues. Therapies that boost or enhance Tregs aim to maintain a healthy balance, potentially offering a targeted way to reduce harmful inflammation without suppressing the entire immune system. Dr. Ooi is developing a new type of Treg therapy, specifically targeting a protein called Smith (Sm), which is linked to severe disease and lupus nephritis (kidney inflammation), a major cause of death in lupus patients. Dr. Ooi (funded by the Lupus Research Alliance) previously successfully engineered Tregs from lupus patient cells to create Smith-specific Tregs called Sm-Tregs. These Sm-Tregs were shown to effectively reduce inflammation and halt the progression of lupus nephritis in a humanized model.

In this new project, Dr. Ooi aims to demonstrate that Sm-Tregs can be manufactured using advanced machines that meet US Food and Drug Administration (FDA) standards. This involves scaling up the production process from small lab-scale batches to larger, clinical-grade batches. The goal is to produce a high-quality, consistent Sm-Treg product that can be used in a first-in-human clinical trial for lupus nephritis patients who do not respond to standard treatments. Dr. Ooi has secured access to state-of-the-art manufacturing facilities and plans to initiate the clinical trial at Monash Health in Australia, leveraging the resources of the Australia Lupus Registry and Biobank.

What this means for people with lupus

Dr. Ooi’s research could lead to a new, targeted therapy for lupus specifically for severe cases and lupus nephritis. This innovative approach has the potential to improve treatment outcomes and quality of life for patients who have not responded to existing therapies.

Antigen-specific regulatory T cells are potent suppressors of pathogenic autoimmune responses and can be used to suppress autoimmune disease (Ooi JD, Nature, 2017). In lupus, autoreactivity to the Smith (Sm) antigen leads to increases in disease severity including the development of lupus nephritis, a major cause of death in patients. Autoreactivity to the Sm antigen is associated with the inheritance of two HLA-DR types: HLA-DR15 (HLA-DRB115:01) and HLA-DR3 (HLA-DRB103:01). This means that there is a clear T cell involvement in disease and that the development of a TCR-Treg therapy restricted to just these two HLA-types has the potential to treat up to 90% of lupus patients with Sm-autoreactivity.

In work previously funded by the LRA, first as a Novel Research Grant then as an Innovation Award, we identified the key dominant T cell epitope of the Sm antigen, including solving the peptide-HLA crystal structure. Then, using high-throughput single-cell sequencing, we identified and validated Sm-specific T cell receptors. We transduced the lead Sm-TCR onto lupus patient derived Tregs to generate Sm-specific Tregs (Sm-Tregs), and demonstrated that the Sm-Tregs effectively and specifically switched-off lupus patient derived pro-inflammatory autoimmunity. Furthermore, we developed a humanised model of lupus nephritis using patient cells and showed that the Sm-Tregs could be used to halt the progression of lupus nephritis. This first-in-kind high-impact work was published in Nature Communications (Eggenhuizen PJ et al, Nat Commun, 2024), and received significant news coverage worldwide (Almetric >220). Furthermore, we currently have two published PCT patent applications currently at national phase worldwide to protect the use of Sm-Tregs to treat lupus.

In this project, we aim to demonstrate that the Sm-Treg cell product can be manufactured within GMP-ready closed system machines, so that we can attract investment to conduct a first-in-human clinical trial to treat lupus nephritis patients refractory to standard of care. We will upscale our manufacturing processes from 100ml of blood to 500ml of blood and transfer our current labscale bench-top processes to closed-system automated state-of-the-art GMP-ready machines. This work will be part of the INDenabling studies we perform to demonstrate that the Sm-Treg product can be manufactured to FDA-approved standards in regards to yield of TCR-transduced Tregs, viability, purity, reproducibility, and suppressive capacity. We have secured access to the latest closed system machines in GMP-ready cell manufacturing through an industry partnership at a fraction of the cost. If successful, we’ll be able to initiate the clinical trial at our site here at Monash Health, Australia. We have identified the lupus patients within our Australia Lupus Registry and Biobank and have all the necessary facilities and regulatory accreditation to manufacture and administer the Sm-Tregs into patients in a Phase 1 trial.