ebf presentation fw immunogenicity sep2018 kromminga 4to3 · ebf presentation fw immunogenicity...
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Clinical relevance of (unwanted drug-induced)
imm
une responsesPresented at the EBF Focus W
orkshop by PD Dr. Arno Kromm
inga
20 September 2018
2
FDA Imm
unogenicity Guidance, 2016
The sponsor should determine the sensitivity of the assay to have confidence
when reporting im
munogenicity rates. Assay sensitivity represents the low
est concentration at w
hich the antibody preparation consistently produces either a positive result or readout equal to the cut point determ
ined for that particular assay.
FDA recomm
ends that screening and confirmatory ADA assays achieve a sensitivity
of at least 100 nanograms per m
illiliter (ng/mL).Although traditionally FDA has
recomm
ended sensitivity of at least 250–500 ng/mL, recent data suggest that
concentrations as low as 100 ng/m
L may be associated w
ith clinical events (Plotkin 2010; Zhou, Hoofring, et al. 2013).
3
ADA characteristics and Characteristics
Concentration and characteristics of the ADA response observed follow
ing weekly
administration of AM
G 317
Higher ADA concentrations and later time
points were associated w
ith lower trough
AMG 317 m
easurements.
Zhou L, HoofringSA et al, AAPSJ, 2013
4
Determination ofADA Sensitivity
Assay RunLinear Fit
Sigmoidal Fit
Asymm
etric Sigm
oidal Fit
Run1OP1
0,9330,922
0,96
0,7610,615
0,615
Run2OP1
1,1261,172
1,212
1,0480,980
0,998
Run1OP2
1,1461,118
1,166
0,9420,756
0,759
Run2OP2
1,0651,069
1,127
0,9970,891
0,938
Mean
1,0020,940
0,972
SD0,125
0,1870,205
Sensitivity: m
ean + (t0.05df*SD) in ng/mL
1,31,4
1,6
LPC1: m
ean + (t0.01df*SD) in ng/mL
1,41,8
2,4
ADA sensitivity as low as low
ng or even sub-ng range be achieved. The question needs to be discussed w
hether or not these high analytical sensitivities are needed or clinically relevant.
5
Induction of Imm
une Responses
Abbas, Lichtman and Pillai, 2016
The induction of imm
une response is cascade of m
ultiple steps and ultimately
leads to highly specific antibodies and T cells.
6
B Cell Activationand Antibody Production
Abbas, Lichtman and Pillai, 2016
The maturation of antibodies results in antibodies w
ith different binding affinities and functionalities.
7
Red: isotypeBlue: cells
Green: various functions Yellow
: epitope recognition
NaturalAntibodies
HolodickNE et al, Front Im
munol, 2017
Natural antibodies are pre-im
mune antibodies
generated in the absence of exogenous antigenic stim
ulation.
Natural antibodies
✓have the ability to exert a protective or regulatory function
✓show
a pre-existing/imm
ediately imm
une responsive.
8
Diverse Roles of Natural IgM
Antibodies
Natural IgM
plays a role in:
✓Direct pathogen neutralization
✓Classical com
plement activation
✓Ag recruitm
ent and priming of
subsequent TI adaptive imm
unity
✓Ab-dependent cell-m
ediated cytotoxicity
✓Apoptotic cell phagocytosis
✓Clearance of DAM
Ps
✓B cell hom
eostasis
Panda S & Ding JL, J Im
munol, 2015
9
(Possible) Roles of Natural IgG &
Natural IgG
Antibodies
Panda S & Ding JL, J Im
munol, 2015
a.Pathogen recognition and clearance, thus controlling inflam
mation by regulating the
production of cytokines
b.Role in Health and Disease:✓
Controlling or exacerbating autoimm
une diseases,
✓Am
eliorating inflamm
ation,
✓Im
mune regulation and hom
eostasis,
✓Developm
ent of safer and more effective
imm
unomodulators.
10
Pre-existingAntibodies
van Schie, Wolbink, Rispens,m
abs, 2015
AntibodiesDirectedTow
ards: ✓
Idiotype(CDR, FR)
✓Isotype
✓Allotype
✓Heterophilic
antibodies
✓Hinge region
✓Carbohydrates
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Clinical Relevance of anti-PEG Antibodies
GorovitsB et al. , AAPSJ, 2016
12
Prevalenceand
ConsequenceofPre-existing
AB
XueL &
Rup B, AAPSJ, 2013
a.10.8%
of all study subjects had detectable pre-existing Abs across studies.
b.13%
of subjects with post-treatm
ent ADA w
ere positive for pre-existing antibodies.
13%
87%
ADA Elevation fromPositive Baseline
ADA Elevation fromN
egative Baseline
ADA+Subjects from
Studies Associated with Pre-existing Abs
PercentageN
umberof
Subjects
In all studysubjects
10.8%(103/950)
In healthy volunteers3.6%
(3/84)
In all disease populations11.5%
(100/866)
In disease populations excluding RA
8.5%(38/446)
InRA patients
14.8%(62/420)
13
Anti-CCP AB Detection Prior to the Disease Onset
Rantapää-DahlqvistS et al. , 2003
Sens(%)
Spec (%)
PPV(%
) N
PV (%)
RAPatients
3498
8286
>1.5 years before sym
ptoms
2598
8084
<1.5 years before sym
ptoms
5298
8589
Early RA70
9891
93
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PredictiveAntibodiesAgainstCCP (in RA)
Accumulated percentage positive sam
ples analyzed before onset of sym
ptoms and at diagnosis.
Kokkonenet al. Arthritis Research &
Therapy 2011
Antibody levels, aspercentage of cut-off valuesbefore and at disease onset
15
Time Course
ofClinical RA Onset
Taylor P et al. Autoimm
une Dis, 2011
Anti-CCP antibodies in the serum
of patients are present as many
as 12 to 14 years prior to the developm
ent of RA. In these studies, 34%
–40% of the RA
patients had anti-CCP+ results prior to disease onset
16
Conclusion
✓Im
mune responses against self or foreign m
ay lead to the formation of detectable antibodies.
✓It is unclear w
hether pre-existing Abs may increase the risk for drug-induced ADA.
✓Antibody form
ation often precedes the clinical onset of imm
une-mediated diseases.
✓Antibody assays cannot be too sensitive.
✓A careful and thorough data interpretation is needed w
hich takes into account the clinical m
anifestation and clinical relevant biomarkers (including PK).
✓The kinetics and type of antibody responses should be m
onitored to assess the risk of developing a treatm
ent-emergent im
mune responses.
✓Post-approval ADA and drug patient m
onitoring should be mandatory.
17
Outlook
–R. Chandler, 1940
“A p
roo
f is alw
ays a
relative th
ing
. It’s an
o
verwh
elmin
g b
ala
nce o
f pro
ba
bilities.”