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Preclinicalimmunogenicitytesting

Christian Ross, Lisbeth Bjerring Jensen, Inger Mollerup

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Immunogenicity studies in the preclinical phase

Scientific background

Risk based approach - planning of the preclinical immunogenicity program

Current aspects of preclinical immunogenicity program

Predictive value of preclinical immunogenicity testing ?

Future aspects of preclinical immunogenicity testing

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IFNEPO

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Varying immunogenicity (bAb) of different IFN-beta preparations in MS

Time (Months)0 3 6 9 12 15 18 21 24 27 30 33 36

Num

ber o

f Ab-

posi

tive

pts.

(%)

0

20

40

60

80

100

IFN-ß1A (Rebif, 1.5MIU x1IFN-ß1B IFN-ß 1A (Rebif, 6MIU x 3)IFN-ß 1A (12MIE x 3) Placebo IFN-ß 1A (Avonex)IFN-ß 1A (Rebif, 6MIU x 3)

Ross et al

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Binding and neutralizing antibodies over time

Time (Months)0 3 6 9 12 15 18 21 24

Bin

ding

(%)

0

10

20

30

40

50

60

70

80

Neu

tral

izat

ion

(%)

0

20

40

60

80

Dis

soci

atio

n (h

ours

)

0

5

10

15

20

25

30

35

Binding 1IU/ml 3IU/ml 10LU/ml Diss.

Ross et al

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Significant variation between laboratories and assays

Protein-G binding capacity (%)

0 20 40 60 80 100

Ant

i-IFN

-ß E

IA (T

iter)

050

100150200250300350400450

High

HighLowLow

Ross et al

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Planning of preclinical immunogenicityprogram

RISK BASED APPROACH

LIKELIHOOD CONSEQUENCE

(for review, Shankar et al, Nature Biotechnology, 2007)

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Assay developmentScreening assayConfirmatory assayNeutralizing/functional assay

Supporting exposure profile in preclinicalanimal studiesPreparation for clinical studies

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Preclinical animal models

InsulinGrowth hormoneEPOIFN

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T-cell epitope models

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Future recommendations

Validate correlation between preclinical analyses and clinical results including the ”Risk-based approach” to immunogenicity.

Guideline requirements should be based on validatedanalyses and data.

Active ongoing interaction between authoraties, pharmaceutical industry, international organizations and research institutions regarding immunogenicity. EIP.

Based on the unclear conclusions from present preclinicalimmunogenicity testing a full clinical program shouldallways be included in drug development

.

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Preclinicalimmunogenicitytesting does not yet show theclinical future in the crystal ball !