Targeted regulatory T cells (Tregs) to treat lupus nephritis

With a previous grant from the LRA, Dr. Ooi studied which specific parts of the body were targeted by the misguided immune system in patients with lupus nephritis, a condition causing inflammation in the kidneys. Lupus nephritis affects approximately half of lupus patients and can shorten life expectancy. Dr. Ooi has pioneered the approach of developing specialized regulatory T cells that may be used as a future treatment for lupus nephritis patients. Regulatory T cells are immune cells that in healthy people stop the immune system’s response once an infection has cleared and prevent the immune system from attacking the body’s own tissues and cells. In a mouse model of lupus nephritis, Dr. Ooi found that the specialized regulatory T cells can suppress the misguided immune response that leads to lupus nephritis. With his current LRA grant, Dr. Ooi will produce and test the effectiveness of “clinical-grade” regulatory T cells on lupus nephritis patient samples as well as in mice with lupus nephritis.

What this study means for people with lupus

Findings from this study will provide a foundation for clinical studies testing a potentially first-in-class therapy for lupus nephritis that uses specialized regulatory T cells to treat and even possibly cure this disease.

Background
Autoimmune diseases, like lupus, are caused by the immune system mistakenly mounting pro-inflammatory responses against specific autoantigens. In a landmark Nature paper, 2017, we showed that autoantigen specific Tregs effectively restore immune tolerance and abrogate disease. Our laboratory has now developed the unique, innovative, capability to genetically-engineer autoantigen specific Tregs. We refer to them as targeted Tregs.

Lupus nephritis is a severe disease manifestation of SLE heterogeneity. Patients with lupus nephritis are at high-risk of developing end-stage kidney failure and have a significant reduction in lifespan. Current approaches, including newly approved biologicals, are ineffective at improving treatment outcomes for SLE patients with lupus nephritis.

In our Novel Research Grant (2018), using high-throughput single cell sequencing we successfully identified a novel dominant autoimmune target that lead to lupus nephritis. Furthermore, using our custom lentiviral vectors and Treg transduction processes, we have genetically engineered therapeutic targeted Tregs specific for the dominant autoimmune target driving lupus nephritis (PCT patent filed).

In this 2021 LIA application, we are seeking to manufacture our targeted Tregs using GMP-ready processes and test the therapeutic efficacy on lupus nephritis patient samples. The ability to prove the efficacy of this targeted Treg approach will determine whether or not we will receive commercial investment to initiate clinical trials.

Long-term objective
To develop a targeted Treg therapy that cures lupus

Specific Aims:
1. Manufacture targeted Tregs using GMP-compliant processes
We have designed a new scalable GMP-ready targeted Treg manufacturing process. Briefly, Tregs are isolated from patient PBMCs using a magnetic-based approach. Then, expression of the T cell receptor (TCR) is achieved through transduction with a custom lentiviral vector. This Aim will provide necessary data regarding achievable cell doses and target product profile.

2. Specifically suppress autoreactive responses using in vitro cultures
Using this assay, we will be able to specifically determine the effect of our targeted Tregs on suppressing the autoreactive response. Our preliminary data using this protocol has shown that our targeted Tregs effectively stop the autoreactive response against the target autoantigen.

3. Treat disease in vivo using a humanised model of lupus nephritis
We have established a new humanised mouse model of lupus nephritis that enables us to test the efficacy of our targeted Tregs in vivo. In this model, the adoptive transfer of PBMCs from SLE patients with lupus nephritis into immunocompromised NSG-MHC null mice lead to the development of nephritis. In our preliminary data, untreated mice and polyclonal Treg treated mice progressed to severe renal disease while none of the mice treated with our targeted Tregs progressed to severe disease.