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Comparability of a human IgG1 after cell line switching:
A retrospective view
Peter Lloyd
Head of PK-PD, Novartis Biologics
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Outline of the presentation:
Introduction to case study:
IgG PK and mAb-ligand binding models:
- consequences for characterisation of extent and duration of effect
Retrospective analysis:
- can rodent replace NHP in PK studies to explore inherent IgG behaviour?
- can immunogenic potential be detected with appropriate PK and PD
analytical strategies?
- can appropriate clinical strategies during clinical development provide
more definitive information on comparability?
Summary:
- “yes they can”
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Case study:
 IgG1 monoclonal Ab
 binds to and neutralises a soluble cytokine target
- target not detected at baseline in systemic circulation
 cross-reactivity established with marmoset and
human target (similar affinity)
 PK assay for total drug in serum (marmoset / human)
 PD assay for total ligand in serum (human)
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Case study:
Product A
Product B
Product C
Product D
NS0-derived
≥52 mg/mL
Sp2/0-derived
≥65 mg/mL
Sp2/0-derived
≥180 mg/mL
Sp2/0-derived
≥175 mg/mL
- human and
marmoset crossreactivity
Comparability
exercise:
- phys - chem
- PK (NHP)
Comparability
exercise:
- phys - chem
- PK (NHP)
Comparability
exercise:
- phys - chem
-
-
-marmoset: 4
and 26 wk iv,
13 wk s.c.
toxicology and
EFD
Clinical studies
Clinical studies
NS0 = expression cell line (mouse myeloma)
Sp2/0 = expression cell line (mouse myeloma)
HSA = Human serum albumin
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Case study:
Research
Pre-clin
Phase I
Phase II
Phase III
cell line switch
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Phase IV
Case study: PK comparability non-human primate
single sc dose x-over study
n=16 marmosets
ACZ885 Concentration (ng/mL)
mAb concentration (g/mL)
Serum
100000
NS0
 ACZ885
– NSO
SP2/0
 ACZ885
– SP2/0
PK comparability established:
- AUC
- Cmax and tmax
10000
1000
100
0
10
20
30
40
50
Time(days)
(Days)
Time
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Outline of the presentation:
Introduction to case study:
IgG PK and mAb-ligand binding models:
- consequences for characterisation of extent and duration of effect
Retrospective analysis:
- can rodent replace NHP in PK studies to explore inherent IgG behaviour?
- can immunogenic potential be detected with appropriate PK and PD
analytical strategies?
- can appropriate clinical strategies during clinical development provide
more definitive information on comparability?
Summary:
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A simple mAb PK model:
mAb
iv dose
elimination
mAb
slow clearance
V ~ 7L
t½ ~ 300 h (human)
FcRn protects IgG from degradation & explains long
serum half-life
Roopenian and Akilesh.
Nature Reviews Immunology 2007; 7: 715
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Mouse, rat and cyno FcRn recognize human IgG
man
IgG kinetics scale reasonably
well using an allometric approach
non-human primate
NB only when target mediated
disposition is absent
rat
mouse
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A simple mAb PK-PD model:
input ligand
mAb
+
ligand
mAb – ligand
complex
dose
elimination
mAb
elimination
ligand
slow clearance
V ~ 7L
t½ ~ 300 h
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elimination
mAb – ligand
complex
Components of the PK-PD model:
 Inherent pharmacokinetics of the mAb (IgG behaviour):
- species differences often well understood and easily characterised;
good prediction to man
 Binding affinity to the target ligand:
- species differences understood during characterisation of the mAb
 Turnover of the ligand and clearance of the mAb-ligand complex:
- species differences and behaviour of mAb-ligand complex sometimes not well
understood
- if cell surface ligand is not saturated with mAb then the mAb-ligand complex
may be cleared very quickly (target mediated clearance)
- for a soluble ligand the mAb-ligand complex will tend to follow IgG clearance
mechanisms (eg case study)
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Case study: PK-PD model
soluble ligand
1.2
Single dose:
0.01 mg/kg
0.1 mg/kg
1.0 mg/kg
10.0 mg/kg
Free ligand concentration
1.0
0.8
0.6
0.4
mAb
ligand
complex
0.2
0.0
20
40
60
80
100
120
Time (days)
Assumptions
mAb with typical IgG kinetics; Kd = 0.37nM; soluble ligand, turnover (half-life 3h)
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Literature example: cell surface ligand
anti-CD11a mAb – Raptiva (efalizumab)
mAb
complex
ligand
Joshi et al An overview of the pharmacokinetics and pharmacodynamics
of efalizumab: a monoclonal antibody approved for use in psoriasis
J Clin Pharmacol 2006; 46: 10-20
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Summary: Ab-ligand PK-PD binding models
– PK of monoclonal antibodies will generally follow “typical IgG
behaviour” and scale reasonably well to man and/or exhibit Target
Mediated Drug Disposition (TMDD) and be dependent on the amount
of target present and its rate of turnover
– Once maximum ligand binding is achieved then increasing the dose
will primarily increase the duration of response
– The shape of the exposure response curve can be simulated from preclinical data by adjusting parameters in the model (eg binding affinity,
target expression)
– The amount of ligand present and the rate at which it can be replaced
(turnover) will be key drivers of the extent and duration of response
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Case study: consequences for comparability testing
For an antagonistic mAb cleared primarily by IgG mediated clearance
pathways, a study with PK endpoints will explore only inherent IgG
characteristics
this data could be generated equally well in rodents, as rodents clear human
IgG by similar pathways to man
Differences in conventional non-compartmental PK parameters (Cmax,
tmax) at high saturating doses may not impact on efficacy
Binding to target is often not addressed in a PK-only study design
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Literature example: glycosylation pattern (rodent)
Milward et al Effect of constant and variable domain glycosylation on
pharmacokinetics of therapeutic antibodies in mice
Biologicals 2008; 36: 41-47
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Case study: impact of immunogenicity
non-neutralizing
neutralizing
anti-drug antibody
anti-drug antibody
drug
mAb “typical IgG kinetics”
increase in IgG clearance
no effect on target binding
(total ligand, receptor occupancy)
increase in IgG clearance
decrease in target binding
(decrease in total ligand)
Target Mediated Disposition
increase IgG clearance
(change in inflection point?)
no effect on target binding
increase/decrease in clearance?
(change in inflection point?)
decrease in target binding
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Analytical strategy: impact of neutralizing immunogenicity
PK
PD (soluble target) *
a)
Immunogenicity
a)
anti-human IgG
nIG may interfere in the PK and
PD assays; detected as short
PK t½. Immune complexes may
also be cleared more rapidly.
Decrease in total target may
be apparent
mAb (drug)
ligand
residual bioactive drug
b)
drug-ligand complex / total target
residual bioactive drug
c)
capture Ab
or LC-MS
b)
NB: capture Ab has different
ligand binding epitope compared
with the drug and no steric
interference
* - for cell surface target use
receptor occupancy and/or PK
profile
total drug (non-human only)
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c)
nIG may intefere in the PK and
PD assays; detected as increase
/ decrease in exposure.
Decrease in total target may
be apparent
nIG does not interfere in the PK
assay; although immune
complexes may be cleared more
rapidly.
Decrease in total target may
be apparent
Case study: population analysis of clinical data
Phase III clinical study
- incorporate comparability testing into clinical design;
product A (NS0) and B (SP2/0) as covariates (n=35 patients per treatment)
- serum total mAb and total ligand measured with sparse sampling strategy
predict free ligand from PK-PD binding model
- ligand capture (and therefore ligand suppression) will also detect neutralizing
immunogenicity
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Case study: population analysis of clinical data
Typical PK and PD profile from the PK-PD model
Simulation of 150 mg s.c. single dose of Canakinumb
20
40
60
80
Time(days)
Time
(days)
100
10
5
10
5
0
Conclusions for materials
derived from both cell lines:
- similar sc bav
- similar in-vivo KD derived from
clinical PK-PD binding model
- no loss total ligand over time
(ie no evidence of neutralizing
immunogenicity)
1
NSO
----- SP2/0
NS0 cell line
SP2/0 cell line
(pg/mL)
concentration
Serum ligandIL-1beta
conc, pg/mL
Total ligand (PD profile)
1
Canakinumab conc, ug/mL
concentration (g/mL)
Serum mAb
mAb (PK profile)
0
20
40
60
80
100
Time(days)
Time
(days)
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Case study: summary
Can rodent replace NHP in PK studies to explore inherent IgG behaviour?
Industry perception and concern that NHP primate PK studies are necessary
is driving acceptance that these will be the norm;
however, for this case study (mAb targeted against a soluble ligand), preclinical studies in NHP with PK-only endpoint could probably be replaced by a
PK study in rodent, even when the mAb does not bind the target in rodent
(only the inherent IgG behaviour is characterised)
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Case study: summary
Can immunogenic potential be detected with appropriate PK and PD
analytical strategies?
If total ligand capture can be easily measured, then neutralizing
immunogenicity should be apparent as a decrease in total ligand;
this can easily be monitored in Phase III clinical trials; providing a robust
assessment of immunogenic potential;
additional neutralizing immunogenicity assays are probably not required
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Case study: summary
Can appropriate clinical strategies during clinical development provide
more definitive information on comparability?
doses are often given at saturation of target ligand binding and differences in
dose therefore affect duration of action rather than extent; conventional PK
parameters to assess comparability (eg Cmax and tmax) may not be
appropriate
clinical studies with target capture and appropriate analytical strategy are
more informative than pre-clinical studies regarding comparability of efficacy
and immunogenic potential
during drug development comparability testing can be built into clinical study
design
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THANK YOU for your attention
Acknowledgements:
Jennifer Sims (Head Translational Sciences and Safety, Novartis Biologics)
Phil Lowe (Modelling and Simulation, Novartis)
Annette Zaar (Head of Immunogencity, Novartis Biologics)
Fabienne Deckert (Head of PK-PD Bioanalytics, Novartis Biologics)
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