Biologics in autoimmune diseases

Question 1

Anti TNFa therapies

Answer 1

TNFa is a major cytokine that mediates inflammation

adalimumab (40mg SC injection every 2 weeks), infliximab (3mg/kg IV at 2, 6, then 8 weeks), certolizumab, and golimumab are mAbs against TNFa

Etanercept (25mg SC injection 2xweek) is a fusion protein of 2 soluble TNFa receptors that binds to TNFa. “mops up” TNFa

Question 2

Targeting of IL-6

Answer 2

IL-6 can act at plasma membrane IL-6Rs to induce inflammatory signalling. Acts through JAK, STAT and MAPK

IL-6 can also bind to soluble IL-6 receptors (sIL-6R) which then binds to cell-membrane gp130. this activates inflammation pathways. excessive activation causes cytokine storm.

tocilizumab and sarilumab bind to sIL-6R to prevent IL-6 binding. Prevents gp130 activation. used in RA and tocilizumab used against COVID-induced cytokine storm.

Siltuximab, sirukumab and clazakizumab bind to the IL-6 to prevent binding of IL-6R

Olamkicept is an EC portion of gp130 fused to the FC of a human IgG antibody. it binds to the IL-6/sIL-6R complex to prevent it binding to gp130

olokizumab binds to IL-6 preventing binding to gp130. does so by binding to a region in IL-6 that interacts with gp130

Question 3

Abatacept

Answer 3

T-cells are activated by antigen presenting cells (APCs) by interactions of CD80/86 on APCs that interact with CD28 and CTLA-4 on T-cells.

Abatacept is an antibody for CD80/86 preventing its binding to CD28. it is a fusion protein of IgG and CTLA-4.

Effective for RA but not recommended by NICE due to costs

Question 4

Interleukin-1 antagonists

Answer 4

Anakinra is a recombinant form of the endogenous: interleukin-1 receptor antagonist (IL-1Ra). this prevents IL-1 activating IL-1R

Question 5

JAK inhibitor

Answer 5

Tofacitinib.

Janus kinase involved in cytokine signalling and gene transcription.

only recommended if the company agrees to lower the price on it.

Question 6

Targetting B-cells

Answer 6

pfatumumab, ocrelizumab and rituximab are anti-CD20 antibodies.

B-cells play major role in pathogenesis of MS. sees infiltration of the brain by B-cells, which then produce antibodies against myelin.

CD20 is a TM protein present on B-cells. these mAbs cross link the CD20 on the B-cells, signalling to macrophages and NK cells that the B-cell needs to be removed.

given every 6 months.

Rituximab is also used in RA.