The Complement System: Friend and Foe
Dick Wells, Odette Cancer Centre
Disclosures
I have received honoraria and research funding from
Alexion
Overview
Complement function and regulation
Implications of chronic uncontrolled complement
activation
PNH, aHUS diagnosis and management
Design of complement
Now known to be at least 27 proteins
Inactive state
(serum)
Activation and
amplification (3 pathways)
Localization on membrane
surfaces Function: LYSIS
Regulation
Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4:359-395; Ross GD. Introduction and history of complement research. In Ross GD, ed.
Immunobiology of the Complement System. Orlando, FL: Academic Press, Inc; 1986:1-20; Walport MJ. N Engl J Med. 2001;344:1058-1066.
Initiation Infection Surgery Autoimmune disease Pregnancy
The Complement Cascade
Pro
xim
al
Term
inal
C3 + H2O - ALWAYS ACTIVE (chronic)
Amplification
Regulation of Complement
Regulation gives specificity
Activated complement
Self Non-self
Complement attacks both self and non-self
Host cells are protected by complement regulatory proteins
Control of complement
Direct inhibition of enzyme
activity
Disruption of enzyme
complexes
Degradation of C3b and C4b
Prevention of MAC assembly
C1 inhibitor
CD55
Factor I and cofactors
(Factor H, C4 binding
protein, MCP, TM)
CD59
MCP = membrane cofactor protein; TM = thrombomodulin; TCC = terminal complement complex.
Factor I and co-factors: Soluble and Membrane Bound Complement Regulators
Confidential – For Internal Use Only 9
CD55 and CD59:
Membrane Bound Complement Regulators
C3b
C3b
C3b
Bb
BC3b
Bb
C3b
C5convertase
RBCMembrane
C5b
C5
C5a
Anaphylotoxins
Platelets
Neutrophils
C3convertase
Classical
Alternave
Lecn
MAC
Bb
C3b
CD59CD55
Chronic Uncontrolled Complement Activation
Leads to Devastating Consequences P
roxim
al
Term
inal
-
C3 + H2O - ALWAYS ACTIVE (chronic)
Amplification
Anaphylaxis
Inflammation
Thrombosis
Consequences
Cell Destruction
Inflammation
Thrombosis
Consequences
-
Consequences of deregulation
Diseases of disordered complement
regulation
PNH aHUS
Aetiology Acquired PIGA mutation,
resulting in deficiency of
CD55 and CD59
Inherited mutation or
acquired inhibitor of
Factor I or co-factors
Tissue affected Haematopoietic Endothelial
Age at
presentation
Any Any
Pathogenetic
event
Chronic attack on vulnerable tissue by activated
complement
Clinical effects Intravascular haemolysis,
thrombosis, renal failure,
pulmonary HT, fatigue,
smooth muscle spasm, pain
Thrombotic
microangiopathy, renal
failure, neurological
abnormalities
Loss of Factor I and co-factors:
Chronic Uncontrolled Complement Activation
Simple triggers, including common infections and stressors further accelerate complement over-activity
Keir L, Coward RJ. Pediatr Nephrol. 2011;26(4):523-33.
14
Atypical HUS
Very rare (about the same as PNH)
Inherited deficiency or acquired inhibitor of I, H, TM, etc
May present from infancy to old age
Presents like TTP: microangiopathic haemolytic anaemia with thrombocytopenia, RBC fragmentation, renal failure
But ADAMTS13 >10%
Transient response to PLEX
Progresses to ESRD; recurs in transplant kidneys
Platelets
Neutrophils
C3b C5 convertase
C5b
C5
C5a
Anaphylotoxins
C3
convertase
MAC
No CD55/CD59
Unrestrained activation of terminal complement…
In PNH Chronic Uncontrolled Complement
Activation Leads to Vasoconstriction and Thrombosis
Adapted from: Gladwin MT et al. Free Rad Biol & Med. 2004;36(6):707-717; Rother RP et al. JAMA. 2005;293:1653-1662.
Chronic hemolysis
Platelet activation
Local vasoconstriction
CLOT Platelet
Activation
Leukocyte
Activation
Chronic
Uncontrolled
Complement
Activation
C5a C5b-9
C5b-9
[NO]
Inflammation
Platelet
Aggregation
Chronic Hemolysis
Inflammation
Endothelial cell injury
Systemic thrombosis
Summary: Disorders of Complement
Regulation
Complement
is always on
CD55/59 Factor I Erythrocytes Endothelium
TMA Intravascular
haemolysis
Diagnosis
PNH
Bone marrow failure
Weird thrombosis
Intravascular haemolysis
Haemoglobinuria
aHUS
MAHA (like TTP)
ADAMTS13>10%
Not responding to PLEX
HIGH-SENSITIVITY FLOW GENETIC TESTING*
Treatment of complement
regulation disorders
C5
Pro
xim
al
Te
rmin
al
1. Soliris® (eculizumab) Product Monograph, 2013.; 2. Rother RP et al., 2007.; 3. Walport MJ, 2001.; 4. Figueroa JE and Densen P, 1991.
C5a
ECULIZUMAB
• Binds with high affinity to C51,2
• Terminal complement: C5a and C5b-9
formation blocked1,2
• Proximal functions of complement
remain intact1,2:
• Weak anaphylatoxin2,4
• Immune complex clearance2
• Microbial opsonization2
Complement cascade2,3
C5b-9 C5b
C3 C3a
C3b
Eculizumab blocks terminal complement
Eculizumab blocks haemolysis in PNH
1. Hillmen P et al., Blood 2007; 110:4123-4128; 2. Hillmen P et al., Br J Hematol 2013; 162:62-73; 3. Soliris® (eculizumab) Product Monograph, Alexion
Pharma Canada, February 2013.
Crossover
• 87.6% serum LDH reduction 1 month after treatment initiation1
• 86.9% decrease in hemolysis maintained for 36 months1
Copyright © 2007 American Society of Hematology.
Reprinted with permission.
Impact on survival in PNH
.
1. Hillmen P et al., 1995.; 2. Hill A et al., 2012.; 3. Soliris® (eculizumab) Product Monograph, 2013.
100
80
60
40
20
0
0 5 10 15 20 25
Years after diagnosis
Pa
tie
nts
su
rviv
ing
(%
)
Pre-eculizumab from time of
diagnosis in 80 patients with PNH1
Age- and gender-
matched controls
Patients with PNH
• Despite best supportive care, 5-year
mortality rate was 35%1
PNH patients on eculizumab compared with
age- and gender-matched controls2*
Time (years)
• Hazard ratio = 2.24 (p = 0.013)
20
40
60
80
100
2 4 6 8 10 0 0
Age- and gender-matched
normal population
Soliris®-treated PNH population
*Survival after 10 years is slightly inferior to controls with causes of
death related to bone marrow failure and not hemolysis or thrombosis.
Copyright © 2012 American Society of
Hematology. Reprinted with
permission.
Petra Muus et al. Blood 2013;122:2186
©2013 by American Society of Hematology
aHUS: Improvement in GFR with eculizumab treatment
Wrap-up
Complement: friend and Foe
Complement is an important part of the innate immune system
Always ‘on’, ramped up when needed
Multiple complement defense proteins protect host tissues
Acquired or congenital deficiencies in complement defense proteins
CD55/59 PNH
Factor I and friends aHUS
Complement inhibition with eculizumab is effective treatment