The complement system is a vital part of the innate immune system that acts as the body’s first line of defence against infections.1 But what happens when it’s not properly regulated? There is a wide range of complement-mediated diseases, many of which have a devastating impact on people’s lives and can even be fatal.1,2 With limited treatment options for this complex set of diseases, understanding the science behind the complement system is key to addressing the challenges faced by people with this type of disease.
The complement system is so called because it complements (or enhances) the body’s ability to fight disease.1 It’s like an amplifier for the immune system, helping it to remove any foreign microorganisms or damaged cells. The complement system is made up of more than 30 proteins, which exist in an active balance and interact with one another in a chain, or ‘cascade’, of events that lead to the destruction of pathogens, foreign substances such as bacterial cells, viruses and damaged tissue. It is tightly regulated to prevent any damage to healthy cells. When functioning correctly, the complement cascade stops once the infectious threat is removed.1
An important step in the complement cascade is the formation of a pathogen-killing structure called the membrane attack complex (MAC), which punctures lethal holes in target cells. The initial step of MAC formation is triggered when a complement system protein known as complement 5 (C5) is cut into two molecules, one of which combines with other components in the complement system.2
Life-altering complications in the complement system
However, the complement system doesn’t always run smoothly. In some people, abnormal regulation disrupts the balance of the proteins, which can lead to the complement system mistakenly destroying healthy cells and tissue.1 This can cause a range of complement-mediated conditions, from relatively common to extremely rare diseases, many of which can be life-altering.2 These diseases can be associated with debilitating symptoms that people may experience throughout their lifetime, presenting a significant burden on them and their families.3 Some people require extensive or life-long treatment, which can be invasive and inconvenient, and might not always eliminate symptoms completely.4
Paroxysmal Nocturnal Haemoglobinuria – a rare, blood cell-destroying disease
Paroxysmal Nocturnal Haemoglobinuria (PNH) is a rare and life-threatening blood condition, where a mutation in bone marrow stem cells causes red blood cells to be produced without certain proteins on their surface. The absence of these specific proteins causes the complement system to recognise the red blood cells as foreign, kicking off the cascade of events that ultimately leads to their destruction.5,6
While the symptoms and complications of PNH can vary greatly from person to person, they can dramatically affect quality of life.3 The most common problems associated with the condition are anaemia, fatigue, blood clots and kidney disease, as well as bruising, shortness of breath and headaches, which may come and go without warning, throughout a person’s life.5 Although PNH can develop at any age, it is often diagnosed in people around 35-40 years old, which means many people will suffer the effects of the disease for decades.3
The current standard of care for PNH works by targeting the C5 protein in the complement system, thereby restricting the system from destroying healthy red blood cells.4 While this has been shown to be effective, it currently involves frequent, life-long intravenous infusions. Furthermore, as the current standard of care has not been able to successfully target a sufficient number of C5 proteins, some people may still experience disease symptoms,7,8 and a small proportion of the treated population are resistant to the standard of care treatment or require high doses to achieve adequate symptom control.4,9,10
Roche in complement-mediated diseases
Roche has a history of developing innovative antibody therapies to address some of the highest unmet medical needs in haematology. Today, we continue to invest in our effort to bring innovative treatment options to people with diseases of the blood, including PNH, where treatment options are limited.
To combat complement-mediated diseases such as PNH, understanding the intricacies of the complement system while seeking to address the challenges faced by people affected is key. At Roche, we are committed to understanding the role C5-activation plays in the pathogenesis of complement-mediated diseases. We believe that by matching our scientific expertise with our patient-focused philosophy, we can potentially transform the lives of people living with these conditions.
- Noris M, Remuzzi G. Overview of complement activation and regulation. Semin Nephrol. 2013;33:479-492.
- Fukuzawa T, et al. Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases. Sci Rep. 2017;7:1080.
- Groth M, et al. Development of a disease-specific quality of life questionnaire for patients with aplastic anemia and/or paroxysmal nocturnal hemoglobinuria (QLQ-AA/PNH)—report on phases I and II. Ann Hematol. 2017; 96(2): 171–181.
- Harder M, et al. Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation. Blood. 2017;129:970-980.
- National Organization for Rare Diseases. Paroxysmal nocturnal hemoglobinuria. [Internet; cited December 2020] Available from: https://rarediseases.org/rare-diseases/paroxysmal-nocturnal-hemoglobinuria/.
- Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124:2804-2811.
- Risitano AM, et al. Anti-complement Treatment for Paroxysmal Nocturnal Hemoglobinuria: Time for Proximal Complement Inhibition? A Position Paper From the SAAWP of the EBMT. Front Immunol 2019;10:1157;
- Hill A, et al. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood. 2005;106:2559–65;
- Röth A, et al. The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria. Blood. 2020;135 (12):912–920.
- Brodsky RA. How I treat paroxysmal nocturnal hemoglobinuria. Blood. 2009;113 (26):6522–6527.