Principles of biological drugs in SLE

Question 1

What biologic drugs are used in SLE?

Answer 1

• Rituximab
• Belimumab
• anti-IFNa

Question 2

Rituximab?

Answer 2

• anti-CD20
• monoclonal antibody
• chimeric antibody composed of human and murine components
• it leads to complement dependent cytotoxicity where antibody binds to CD20 and leads to activation of classical complement cascade, leading to MAC formation and B cell depletion
• It can also lead to antibody dependent cellular cytotoxicity where it binds to FCyRIII on NK cells and other cells
• CD20 is expressed only on certain B cell populations, not on stem cells, pro-B cells and plasma cells. This allows repopulation of V cells when drug is stopped and production of Ab against other antigens (Leonardo 2013)
• It is successful in around 50% of cases. It can be unsuccessful because of complement components deficiency e.g. C1q or C3, C4, FcyR polymorphisms, changes in CD20 surface expression or changes in lipid raft structure
• There are new type 2 anti-CD20 antibodies produced e.g. Obinutuzumab which is not complement dependent but it is dependent on antibody-dependent cellular cytotoxicity and has less side effects (Freeman 2018)

Question 3

Belimumab?

Answer 3

• anti-BAFF
• Mice KO of BAFF have deficient B cell development and maturation
• BAFF overexpression leads to autoimmunity
• High BAFF levels allow auto reactive B cells to escape apoptosis
• SLE patients have higher BAFF expression than healthy controls (Dillon 2010)
• Targets soluble BAFF not membrane bound
• Monoclonal IgG, fully human
• neutralises circulating BAFF
• blocks BAFF-BAFFR interaction
• Serum BAFF levels rise following rituximab so usually rituximab will be combined with belimumab

Question 4

Anti-IFNa?

Answer 4

• There is increased IFN in SLE and other autoimmune conditions and it is associated with autoantibodies, arthritis and nephritis
• IFN are divided into 3 types: type 1; IFNa, IFNB, IFNk, type 2; IFNy, type 3; IFN^. Type 1 and 3 have role in SLE. Type 1 receptor is divided into two units IFNAR1 and IFNAR2. Engagement of IFNAR leads to activation of JAK and phosphorylation of STAT
• Anifrolumab is a human IgG which targets IFNAR receptor. It results in internalisation of IFNAR and inhibits phosphorylation of STAT1. It blocks signalling of all type 1 interferons and inhibits pDCs mediated plasma cell differentiation (Riggs 2018)