Clinical outcome of Immunogenicity in RA...

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

Factors influencing immunogenicity

Factors influencing immunogenicity

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

Effect of foreign amino acid sequences on the

immunogenicity (Antibody therapeutics)

70% human 95% human 100% human

Sue Richards Immunogenicity Summit 2011

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



mouse epitopes on the Fab regions,

both the framework regions (FR) and the CDR



Mouse epitope on drug CDR



ADAs can also be induced against IgG allotypes

Are the variable regions immunogenic including humanized and full human antibody therapeutics?

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



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

No evidence of Neutralizing antibody for Etanercept

Anti-Etanercept Ab

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.

TNF- Independent or

Incomplete blocking of TNF ?

Persistent disease

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.

Effect of immunogenicity on efficacy

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


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


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

http://www.ncbi.nlm.nih.gov/pubmed/21486979






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

.


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


Anti-drug antibodies have a large impact on

treatment in clinical practice:

•Lower functional drug levels

•higher disease activity

•Less remission

Effect of immunogenicity on safety

Adverse effects caused by immunogenicity

• Type Ⅰ allergy

• Infusion reaction

• Type Ⅲ allergy

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

Infusion reaction

Correlation between incidence of anti-infliximab antibody

and infusion reactions


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


Type Ⅲ allergy

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）

Type Ⅲ allergy reported in Infliximab

skin rash, diffuse joint pain, muscle pain, fatigue

”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



100

0 60

(％)

80

60

40

20

0 10 20 30 40 50



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)


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

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