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N oard Meeting
9th May 2013
Westin Hotel
Naonobu Sugiyama MD, PhD
Rheumatologist
Pfizer Japan Inc.
Medical Affairs
Clinical outcome of Immunogenicity in RA treatment
A list of content
1. Factors influencing immunogenicity
2. Effect of immunogenicity on PK
3. Effect of immunogenicity on
clinical outcome in RA treatment: efficacy
4. Effect of immunogenicity on
clinical outcome in RA treatment: safety
Immune Function of Patients
Many cancer patients receiving chemotherapy are declining in immune function and therefore, less likely to develop an antibody response than normal patients. (Infliximab)
Frequency, duration ,Route of administration
(binding anti-IFN-β1a antibody)
• Frequency
• Duration
• Routes of Administration Susceptible to Antibody Formation
Subcutaneous>Muscular>Intravenous
Japanese Western
G1m17 84% 29%
Jefferis R et al. Mabs 2009; 1: 1-7
De Lange et al Clin Hematol
1991; 4: 903-25
G1m phenotype Anti-Adalimumab
positive rates (%)
3,3 10
3,17 14
17,17 41
Bartelds GM et al. Arthritis Res
Ther 2010; 12(6): R221
Antibody name Antibody
positive (%)
Antibody name Antibody
positive (%)
Muromab 25% (24) Alemtuzumab 1.9-8.3%
Arcitumomab <1% (3./400) Omalizumab <0.1% (1723)
Fanolesomab 0-16.6% (30-54) Efalizumab 6.3% (1063)
Imcriromab <1% (914) Bevacizumab 0% (~500)
Carpomab 8%-19% (27-239) Ranibizumab 1-6%
Nofetumomab 6% (53) Eculizumab 2% (196)
Ibritumomab 1.3% (446) Natalizumab 9% (627)
Tositumomab 11% (230) Cetolizumab pegol 8% (1509)
Abciximab 6-44% (36) Tocilizaumab 2% (2876)
Rituximab 11% (2578) Canakinumab 0%
Basiliximab 1-2% (138-339) Adalimumab 2.6-26%
Infliximab 10-15% Panitumumab 4.6%
Cetuximab 5% (1001) Golimumab 4% (1425)
Dacilizumab 14-44% Ofatumumab 0%
Trasutuzumab <1% Ustekinumab 2% (2876)
Palivizumab 0.7-2% (1002-639) Denosumab <1% (8113)
Gemtuzumab 0% (277)
Antibody positive rates in patients treated with antibody therapeutics approved by FDA
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Mouse
antibody
Chimeric
antibody
Humanized
antibody
Full Human
antibody
Replacement of mouse-derived sequence with human-derived sequence reduces antibody
positive rates. But, there are some full human antibody therapeutics whose the antibody
positive rate is not reduced to o%.
11
Molecular structure and biochemical and mechanistic profile of the 5 TNF antagonists for RA treatment
Material intended for Medic-to-Medic communications ONLY. Not to use for promotion. Version 1 Mar 2011
Infliximab Etanercept Adalimumab Certolizumab Golimumab
Class Monoclonal
antibody
Fc-Fusion
protein
Monoclonal
antibody
Monoclonal
antibody
fragment
Monoclonal
antibody
Structure Mo/Hu
chimeric IgGIκ
Hu sTNFR2-
Fc1
Hu IgG1κ PEG-Hu IgG1κ
Fab1
Hu IgG1κ
Molecular weight (kDa) 150 150 150 ~95 150
Specificity TNF TNF/LT TNF TNF TNF
TNF ligands sTNF, tmTNF sTNF, tmTNF sTNF, tmTNF sTNF, tmTNF sTNF, tmTNF
infliximab etanercept adalimumab
Murine
Fv
Human
Fc1
Human
TNFR2
Human
Fc1
PEG
Humanised Fv
(murine CDRs)
Fab1
Polyethylene
glycol
certolizumab
pegol
golimumab
Human
Fc1
Human
Fv Human
Fv
Huma
n Fc1
Adapted from: Tracey D, et al. Pharmacol Ther 2008;117:244-279.
CDR, complementarity–determining region; Fab, fragment antigen-binding;
Fc, crystalline fragment; Fv, variable fragment; Hu, human; IgG, immunoglobulin G;
LT, lymphotoxin; Mo, mouse; sTNF, soluble tumour necrosis factor;
tmTNF, transmembrane tumour necrosis factor; TNFR, tumour necrosis factor receptor
Potential mechanisms of immunogenicity of anti-TNF antibody constructs
Scandinavian Journal of Gastroenterology, 2009; 44: 774781
Potential mechanisms of immunogenicity of anti-TNF antibody constructs
Scandinavian Journal of Gastroenterology, 2009; 44: 774781
mouse epitopes on the Fab regions,
both the framework regions (FR) and the CDR
Potential mechanisms of immunogenicity of anti-TNF antibody constructs
Scandinavian Journal of Gastroenterology, 2009; 44: 774781
Mouse epitope on drug CDR
Potential mechanisms of immunogenicity of anti-TNF antibody constructs
Scandinavian Journal of Gastroenterology, 2009; 44: 774781
ADAs can also be induced against IgG allotypes
Harding FA et al. mAbs 2010 2:3 256-265
The response and positive rates at CDR regions are higher than those to framework.
Measurement of T cell response to CDR and frame work regions
in humanizied and fully human antibodies by T cell assay
Potential mechanisms of immunogenicity of anti-TNF antibody constructs
Scandinavian Journal of Gastroenterology, 2009; 44: 774781
Idiotopes on ‘‘fully human’’
antibody constructs can also induce anti-idiotypic ADA
Influence of ADA to trough level, safety, efficacy in RA treatment
Etanercept Infliximab Adalimumab Golimumab Certolizumab
Pegol
ADA 0~5.6% 10~50% 0.72~87% 0~7.0% 5~8.1%
Association with serum trough
level ―
Inversely
correlated
Inversely
correlated
Inversely
correlated
―
Association with
efficacy
NR Inversely
correlated
Inversely
correlated
Inversely
correlated
Inversely
correlated
Association with
AE
NR Associated with
infusion-related reactions NR NR ―
Association with MTX
― Inversely associated with use and dosage
Inversely associated with use and dosage
Inversely associated
with use and dosage
―
Vincent, F. B. et al. : Ann Rheum Dis 72(2):165,2013
125I-etanercept
Anti-etanercept IgG4
Anti-IgG4-sepharose
IgG4-ABT
Etanercept-biotine
Anti-etanercept
Etanercept
Bridging ELISA
125I-etanercept-F(ab’)2
Anti-etanercept
Protein A sepharose
ABT
125I-etanercept
Anti-etanercept
Etanercept coupled
to sepharose
2-site RIA
No anti-etanercept detected
Jamnitski A, Jamnitski A, et al. Data on file
With other ADA tests at other centers, ADA’s against
etanercept were detected, which were non-neutralising
Disease activity:DAS 28 score
• Swollen joints
• Tender joints
• General health
• ESR
Prevoo MLL, et al. Arthritis Rheum 1995;38:44–48.
Copyright ©2007 BMJ Publishing Group Ltd. de Vries MK, et al. Ann Rheum Dis 2007;66:1252–1254.
Serum trough infliximab level for responders (n = 21; 8.2 mg/l) and non-responders (n = 17; 6.3 mg/l) according to the ASAS-20 response criteria, at week 54 (p = 0.018)
30
20
10
0
Seru
m tro
ugh iIn
flix
imab level (m
g/l)
Responders Non-responders
p=0.018
Ankylosing spondylitis : infliximab levels and
response
Detection of ADA
van Schouwenburg, P. A. et al. Nat. Rev. Rheumatol. advance online publication 12 February 2013; doi:10.1038/nrrheum.2013.4
27
Infliximab trough levels in serum of patients with RA varied considerably after intravenous infusions of a standard dosage of infliximab, both initially and after the appearance of anti-infliximab antibodies
Inter-individual differences in pharmacokinetics and immunogenicity in patients
receiving anti-TNF therapy
Functional serum levels of infliximab (S-Remicade) and ADA levels (percentage bound cpm/total cpm of added radiolabelled
infliximab) were measured in sera from 106 patients with rheumatoid arthritis beginning immediately before start of therapy, before
the third drug infusion 1.5 months after start, and before infusions at time-points 3 and 6 months, respectively. The drug was given at
the recommended dosage of 3 mg/kg intravenously at all time-points
Bendtzen K, et al. Scand J Gastroenterol 2009;44:774-781. ADA, anti-drug antibodies
Relation of Trough and ADA level
0
20
40
60
80
-2 2 6 10 14 18 22 26 30
Weeks
inflix
imab m
g/L
infliximab anti-infliximab
PK model no anti-infliximab detected
Wolbink, data on file Adapted from Wolbink GJ, et al. Curr Opin Rheumatol. 2009;21:211–5.
0
20
40
60
80
-2 2 6 10 14 18 22 26 30
Weeks
inflix
imab m
g/L
infliximab anti-infliximab
PK model anti-infliximab detected
Wolbink, data on file Adapted from Wolbink GJ, et al. Curr Opin Rheumatol. 2009;21:211–5.
Free Serum adalimumab concentrations
in relation to anti-drug Antibodies
Median adalimumab
concentration
0
2
4
6
8
10
12
14
t=0 t=16wk t=40wk t=78wk t=130wk
no AAA
AAA 13-100 AU/ml
AAA >100 AU/ml
p<0.0001* *
Bartelds GM et al. JAMA 2011;305:1460-1468
The more the antibody titers increase, the more the trough values decrease.
Anti-TNF agents: Studies infliximab
• High antibody levels predict dose increase and/or discontinuation of therapy
Material intended for Medic-to-Medic communications ONLY. Not to use for promotion. Version 1 Mar 2011
Anti-infliximab antibody levels (% bound cpm) in sera obtained before the
fourth infliximab infusion (at 3 months)
P values were determined by
Mann-Whitney rank sum test and
are versus patients who
continued to receive infliximab at
the standard dose. Each circle
represents an individual patient;
bars show the median and
interquartile range
Bendtzen K, et al. Arthritis Rheum 2006;54:3782-3789.
Effect of anti-infliximab antibody on the days until subsequent
infusion of infliximab
The infusion is reinstituted in the case of
apparent relapses (increase of diarrhea and
stomachache, decrease of health condition).
Baert F et al. New Engl J Med 2003; 348:601-608
With higher titers, infusion must be more frequent.
0 0
6 14 30 46
30
25
5
15
Weeks
20
10
Responder group (n=26)
Non-responder group (n=14)
2 22 38 54
*
* *
* * * *
*p<0.05、IFX:infliximab
Hoshino M et al., Mod Rheumatol (2012) 22:532–540.
Anti- IFX antibody:14/40 (35%)
Comparison of serum trough infliximab levels between the responder group and the non-responder group.
Seru
m tro
ugh inflix
imab levels
(μ
g/m
L)
The horizontal lines in the columns, the columns, and the vertical lines beside the columns show the median,
the standard deviation, and the range, respectively.
0 0
6 14 30 46
30
25
5
15
Weeks
20
10
Anti-IFX antibody-negative group (n=26)
Anti-IFX antibody-positive group (n=14)
2 22 38 54
* *
* * * *
Anti-IFX antibody:14/40
*p<0.05、IFX:infliximab
Hoshino M et al., Mod Rheumatol (2012) 22:532–540.
Comparison of serum trough infliximab levels between the anti-infliximab antibody-positive group
and the anti-infliximab antibody-negative group.
Seru
m tro
ugh inflix
imab levels
(μ
g/m
L)
The horizontal lines in the columns, the columns, and the vertical lines beside the columns show
the median, the standard deviation, and the range, respectively.
Comparison of serum trough etanercept levels between the responder group and the non-responder group.
0 0
4 8 16 32
7
6
2
4
Weeks
5
3
1
Responder group (n=31)
Non-responder group (n=9)
Anti-ETN antibody:0/40
ETN:Etanercept
Hoshino M et al., Mod Rheumatol (2012) 22:532–540.
Seru
m tro
ugh e
tan
erc
ept
levels
(μ
g/m
L)
The horizontal lines in the columns, the columns, and the vertical lines beside the columns show the
median, the standard deviation, and the range, respectively.
Immunogenicity in a long-term
follow-up cohort of adalimumab
treated rheumatoid arthritis patients
American College of Rheumatology 2010
Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. Bartelds GM, Krieckaert CL, Nurmohamed MT, van Schouwenburg PA, Lems WF, Twisk JW, Dijkmans BA, Aarden L, Wolbink GJ.JAMA 2011
During 156 weeks follow-up, anti-
adalimumab antibodies were detected
(ASSAY IV:ABT)in 76 (28%) patients
0
5
10
15
20
25
30
0 28 56 84 112 140
Antibodies against
adalimumab (%)
Bartelds GM, Krieckaert CL, Nurmohamed MT, van Schouwenburg PA, Lems WF, Twisk JW, Dijkmans BA, Aarden L, Wolbink GJ.JAMA 2011
percentage of patients developing AAA
Jan van Breemen Research Institute | Reade EULAR centre of Excellence in Rheumatology
0
10
20
30
40
50
60
0 14
28
42
56
70
84
98
11
2
12
6
14
0
15
4
time (weeks)
(%)
no MTX
low doseMTX
intermediatedose MTX
high doseMTX14%
22%
35%
50%
Long term measurements of ADA in a group of 99 RA patients. a) The number of patients producing
ADA (gray) or no ADA (white) and the number of missing data (black) in the different time points
during three years of follow-up. b) The accumulative percentage of patients positive for ADA in the PIA
(dotted line) and the ABT (black line) during three years of adalimumab treatment.
0
20
40
60
ABT
PIA
P<0.0005
284 16 52 78 104 130 156
Time in weeks
% A
DA
po
sit
ive
.
Bartelds GM, Krieckaert CL, Nurmohamed MT, van Schouwenburg PA, Lems WF, Twisk JW, Dijkmans BA, Aarden L, Wolbink GJ.JAMA 2011
Sustained remission (DAS28 <
2.6)
p<0.0001
0 50 100 150 200 0.0
0.1
0.2
0.3
0.4
0.5
AAA -
AAA+
Time in weeks
Rem
issio
n p
rob
ab
ilit
y
Bartelds GM, Krieckaert CL, Nurmohamed MT, van Schouwenburg PA, Lems WF, Twisk JW, Dijkmans BA, Aarden L, Wolbink GJ.JAMA 2011
Anti-drug antibodies have a large impact on
treatment in clinical practice:
•Lower functional drug levels
•higher disease activity
•Less remission
Mast cells
Histamine
Leukotriene
Eosinophil chemotractic
factor
IgE
Allergy
FcεR
Drug binds to IgE ADA , transmits signal in
the cell and activates enzymes at cell surface
and in the cells.
Eosinophil
Pathogenic mechanism of typeⅠallergy
Main symptoms・typical diseases of type Ⅰ allergy
• Anaphylactic shock
• Hives
• Allergic rhinitis and dermatitis
• Atopic flare
• Angioedema
• Wheal
• bronchospasm
• Collapse of respiratory・cardiovascular system
• Conjunctivitis
• Asthma
• Acute-onset of stomach ache
TypeⅠ Allergy caused by Adalimumab(prick test )
Weal formation by Adalimumab
Paltiel M et al. N Engl J Med 2008 144(9) 1190-1194
Prick test positive for TypeⅠ Allergy caused by Adalimumab
Correlation between incidence of anti-infliximab antibody
and infusion reactions
Baert F et al. New Engl J Med 2003; 348:601-608
Infusion reactions develop after the 2nd infusion. The correlation is observed between the
incidence of anti-infliximab antibody and infusion reactions.
Infusion reaction correlates with low serum infliximab concentration
and development of antibodies against infliximab
Baert F et al. New Engl J Med 2003; 348:601-608
Inflammation and
tissue destruction
Release of proteases
Complement
Antibody
Antigen
Binding of complement to
antigen and antibody complex
Deposition of immune complex to
tissue → Activation of complement
①destruction of plasma membrane
→Tissue injury
②Accumulation of neutrophil →
Release of proteases and active oxygen
→Tissue injury
Pathogenic mechanism of type Ⅲ allergy
Major diseases of type Ⅲ allergy
• Serum sickness(fever, exanthem, lymphadenopathy, joint pain)
• Chronic rheumatoid arthritis
• Immune complex type of glomerulonephritis
• Systematic lupus erythematosus(joint pain, low fever, fatigue,
oral ulcer, weight loss, lymphadenopathy、splenic ganglion、hyperesthesia optica、poor feeding, etc)
”Survival-on-drug”
Proportion of patients staying on the prescribed medication at any point in time
Measures performance of (new) medications in actual practice
No patient selection other than clinical need
Combined aspects of lack of efficacy(including immunogenicity), safety, and others (practical aspects, patient preference etc)
Adherence to therapy by treatment group
Southern Sweden
Kristensen, L. E. et al.:Arthritis Rheum 54(2):600, 2006
Withdrawal from therapy for any reason
Months
Withdrawal due to adverse events
Withdrawal due to failure of treatment
100
0 60
(%)
80
60
40
20
0 10 20 30 40 50
p<0.001
Log-rank test
p<0.001
Log-rank test
p=0.018
Log-rank test
: Etanercept (n=309)
:Infliximab (n=640)
100
0 60
(%)
80
60
40
20
0 10 20 30 40 50
: Etanercept (n=309)
:Infliximab (n=640)
100
0 60
(%)
80
60
40
20
0 10 20 30 40 50
: Etanercept (n=309)
:Infliximab (n=640)
Estim
ate
d d
rug a
dh
ere
nce
Estim
ate
d d
rug a
dh
ere
nce
Estim
ate
d d
rug a
dh
ere
nce
Months Months
The 3-year drug survival for etanercept was 62.3%
Survival on anti-TNFa therapy (global and by main reasons for discontinuation)
Risk of anti-TNFa discontinuation by clinical features recorded at the beginning of treatment
Marchesoni, A. et al.:Ann N Y Acad Sci 1173:837, 2009
90
80
70
60
40 p:vs. Etanercept、Cox regression model
100
6
LORHEN Registry (Italy)
(%)
50
12 18 24 30 The risk of discontinuing etanercept was lower than the
risk of discontinuing infliximab (all causes) and
adalimumab (adverse events).
The discontinuations due to remission: 0.9%
The causes of discontinuation of anti-TNFa therapy (36%)
Adverse events 18.2%
Lack or loss of efficacy 16.9%
Remission 0.9%
Others 2.0%
Months 0
:Etanercept (n=242)
:Adalimumab (n=303)
:Infliximab (n=519)
36
Lack orl oss of
efficacy Adverse events
HR
(95%CI) p
HR
(95%CI) p
Etanercept
(n=242) 1 - 1 -
adalimumab
(n=303)
1.12
(0.68-1.84) 0.657
2.09
(1.29-3.38) 0.003
infliximab
(n=519)
1.70
(1.06-2.70) 0.027
1.49
(0.93-2.40) 0.101
Su
rviv
al
Conclusions • Immunogenicity to therapeutic antibodies is associated with altered
pharmacokinetics and loss of response
• It determines the outcome on a second anti-TNF
• It is influenced by several factors including concomittant medication (MTX) and genetic factors
• Study reports from Cohorts with anti-TNF agents clearly indicate that immunogenicity affects the efficacy and safety profile of these drugs
• Drug survival demonstrates combined aspects of lack of efficacy(including immunogenicity), safety, and others
• Physicians should become more aware that immunogenicity may severely compromise treatment of their patients with Biologic therapeutics including anti-TNF agents
• Cohorts or Pharma- covigilance is important until prediction of immunogenicity is fairly established