christian ross, lisbeth bjerring jensen, inger mollerup · fs/0142/05 0/.. critical i biovision,...
TRANSCRIPT
FS/0142/05 0/.. Critical I Biovision, April 13, 2005
Preclinicalimmunogenicitytesting
Christian Ross, Lisbeth Bjerring Jensen, Inger Mollerup
FS/0142/05 1/.. Critical I Biovision, April 13, 2005
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
FS/0142/05 3/.. Critical I Biovision, April 13, 2005
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
FS/0142/05 4/.. Critical I Biovision, April 13, 2005
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
FS/0142/05 5/.. Critical I Biovision, April 13, 2005
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
FS/0142/05 7/.. Critical I Biovision, April 13, 2005
Planning of preclinical immunogenicityprogram
RISK BASED APPROACH
LIKELIHOOD CONSEQUENCE
(for review, Shankar et al, Nature Biotechnology, 2007)
FS/0142/05 8/.. Critical I Biovision, April 13, 2005
Assay developmentScreening assayConfirmatory assayNeutralizing/functional assay
Supporting exposure profile in preclinicalanimal studiesPreparation for clinical studies
FS/0142/05 9/.. Critical I Biovision, April 13, 2005
Preclinical animal models
InsulinGrowth hormoneEPOIFN
FS/0142/05 11/.. Critical I Biovision, April 13, 2005
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
.