Lecture 22 – Complement in health and disease

What is Paroxysmal Nocturnal Haemoglobinuria (PNH)?

Rare acquired life-threatening disease of the blood

• Destruction of red blood cells, blood clots and impaired bone marrow function

• Also 3-5% risk of developing leukaemia

What is the mechanism behind PNH?

GPI anchor deficiency

• Glycolipid structure which attaches proteins to the cell surface membrane

• Without GPI anchor, there is no CD55 and CD59

• This causes MAC formation and haemolysis

• Also causes platelet activation and thrombosis 

How can ecluzimab help treat PNH?

Anti C5 antibody

• Binds C5 and prevents its activation

• Does not bind Fc receptors and does not activate complement

Blocks MAC formation, preventing red cell lysis

What is Atypical Haemolytic Uraemic Syndrome (aHUS)?

Generally complement mediated condition

• Destruction of the glomeruli in the kidney

Clinical trials using Ecluzimab for aHUS showed what?

The treatment caused

• Reduced haemolytic activity

• Platelet count returned to normal

  • Reduced blood clotting

• Recovery of renal function 

What are some issues with Ecluzimab?

Risk of infection with encapsulated bacteria due to the loss of MAC formation

• Often patients need to be immunized with polyvalent meningococcal vaccine for protection 

One of the most expensive drugs when it was first used 

Blood cell haemolysis may be stopped but red blood cells are still heavily opsonized by complement 

• So cells are then killed by phagocytosis 

Certain patients with C5 mutations cause Ecluzimab to be unable to bind C5

• This means its not effective in these patients 

What is TT30?

• Ecluzimab-like drug

Cr2 and Factor H fusion protein

• Causes deactivation of C3b which helps suppress the complement system

• TT30 is better at suppressing the alternative pathway than classical pathway

What is Mini-FH?

• Ecluzimab-like drug

Protects red cells in the presence of autoantibodies

• Stops autoantibodies from binding Factor H and depleting all C3

• Acts as a miniature factor H molecule

What was one of the major issues with Mini-FH?

Very short half-life of 1.8-2 hours.

• Makes it not viable as a drug

How was the half-life issue of mini-FH solved?

Addition of a dimerization domain

• Taken from factor H-related (FHR) proteins

• Increased half-life to 8 hours

Between TT30 and mini-FH, which appeared better?

Studies showed mini-FH was better at protecting red blood cells from lysis

• Also didn’t protect bacteria from complement-mediated killing like ecluzimab did

Why was mini-FH not seen as an overall better treatment option?

Despite the increased half-life, it was still too short lived.

• Treatment would have to be injected too often

What is Age-related Macular Degeneration (AMD)?

Causes irreversible sight loss

• Begins as asymptomatic appearance of drusen

  • Focal deposition of acellular, polymorphous debris

What is drusen and where does it occur?

• Focal deposition of acellular, polymorphous debris

• Between the retinal pigment and bruch’s membrane  

What was found in drusen which indicated a possible involvement in AMD?

• Complement proteins identified in drusen  

  • Suggested complement may be involved in the disease 

What genetic polymorphism is linked with AMD development?

FH-Y402H on one allele 

• Gives a 2.3 fold increase in likelihood of AMD development

• Human complement system is therefore potential target

What are two examples of potential therapies for AMD?

• Pegcetacoplan  

• Avacincaptad Pegol 

What is Pegcetacoplan? How can it treat AMD?

C3 inhibitor

• Injected into the eye and stopped the spread of AMD

• Can inhibit the complement system and slow geographic atrophy in the eye

What is Avacincaptad Pegol?

Anti-C5 molecule

• Stops C5 activation and C5a production

• Slows down development of AMD

Why is understanding the genetics of a patient important for treating complement-mediated diseases?

Certain drugs won’t work on certain patients if they have a mutation

• E.g. ecluzimab wont work on patients with C5 mutations

Why is gene therapy a challenge when treating complement-mediated diseases?

Complement can neutralise gene therapies 

• Antibodies and classical pathway activation drive side-effects in Adeno-associated virus (AAV)-mediated gene therapy  

• This makes it hard to deliver the therapy to their target cells