Emerging treatments for SLE

Question 1

What are emerging treatments for SLE?

Answer 1

• IL-2
• CELMoDs
• Inhibiting NETosis
• Targeting pDC-IFN axis

Question 2

Tregs in SLE?

Answer 2

Patients with SLE have reduced Tregs number and in active lupus levels are lower than in inactive lupus (Suen 2009).

Question 3

What is the role of IL-2?

Answer 3

• Development of CD25+CD4+ Tregs is dependent on IL-2
• It is required for differentiation of th2 cells

Question 4

Treatment with IL2?

Answer 4

• Low dose of IL2 can actually be immunosuppressive but it needs to be balanced because high dose IL2 will be stimulatory which we don’t want
• In mice low dose IL2 there is an increase in CD25+ Tregs and they are proliferating more (Humrich 2010)
• There was clinical trial with 60 patients and patients treated with low dose IL2 showed good response and increased SRI4 compared to placebo group (He 2020). In this study Treg and NK cells numbers increased when IL2 was given and then decreased during the break in treatment meaning that most likely treatment would need to be consistent to maintain Treg level
• IL2 also has function on CD8 T cells and development of memory CD8 T cells but could also lead to activation induced cell death so that can reduce T cell clones

Question 5

What are IKZF1 and IKZF3?

Answer 5

• Transcription factors
• IKZF1 = Ikaros it is a checkpoint for pro B cell to pre B cell
• IKZF3 = Aoilos it is needed for memory B cell and plasma cell formation

Question 6

IKZF1 and IKZF3 in SLE?

Answer 6

In SLE there are genetic abnormalities in IKZF1 and IKZF3 which are associated with higher susceptibility to lupus.

Question 7

How can we target IKZF1 and IKZF3?

Answer 7

CELMoDs is a group of drugs that rely on E3 ubiquitin ligase complex which ubiquitinate proteins to mark them for degradation. CELMoDs bind this complex to other proteins leading to their degradation
- e.g. is Iberdomide which reduces B cell development with no effects on T cells. It stops differentiation of plasma blasts (Lipsky 2022)

Question 8

How can we target pDC-IFN axis?

Answer 8

• We can target NETosis
• Or we can target pDCs
• Or we can target IFN

Question 9

How can we target NETosis?

Answer 9

• PAD inhibitors
• Metformin

Question 10

How can we target pDCs?

Answer 10

• Bcl2 inhibitors (Bcl2 is antiapoptoticm so inhibiting it leads to apoptosis of pDCs) (Zhan 2015)
• anti-BDCA2 antibodies which lead to BDCA internalisation and decrease in type 1 IFN production (Dzionek 2001) e.g. Litifilimab
• IFN vaccine - IFNa coupled with carrier protein (Zagury 2009). There was a clinical trial in humans and showed decrease in IFN gene signature but no clinical benefit
• JAK inhibitors e.g. tofacitib or baracitinib. They showed efficacy in mouse model decreasing ANA, proteinuria and skin lesions (Furumoto 2017) but in humans they did not work as well as in mice plus they gave dangerous side effects like thrombosis (Wallace 2018)
• TYK2 inhibitors - ell Deuctavacitinib is explored in clinical trial. TYK2 is downstream from JAK. It showed increased reponse rate without dangerous side effects (Morand 2023)