immunogenicity
DESCRIPTION
Wadhwa presentationTRANSCRIPT
12-4-2011
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Meenu Wadhwa, PhDCytokines and Growth Factors Section, Biotherapeutics Group,
NIBSC - HPA
United Kingdom
Immunogenicity: What
Do We Know and What
Can We Measure?
Conflict of Interest DisclosureMeenu Wadhwa, PhD
Has no real or apparent
conflicts of interest to report.
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Biotherapeutic Products
• Biotechnology derived products have been
successful for therapy of various diseases
– Hormones, enzymes, coagulation factors, cytokines
– Fusion proteins, monoclonal antibodies
• Despite their benefits, therapeutic proteins
have the potential to induce an immune
response due either to their−Foreign nature if of exogenous origin
or
– Due to recognition as non-self
Immunogenicity Profile of Therapeutics
Product Name Protein Indication
% Patients with
Immune Response
Intron A
Roferon
Pegasys
PegIntron
IFN-α2a Hepatitis C
7
25
9
1
Betaferon
Avonex
Rebif
IFN-β Multiple Sclerosis
25 – 45
2 – 6
12 – 28
Eprex
Neorecormon
Procrit
Aranesp
Epo Anemia Rare
Neupogen
NeulastaG-CSF
Myeloregeneration,
neutropeniaNot detected
Leukine GM-CSFMyeloregeneration,
immunostimulation2 – 95
Proleukin IL-2 Oncology 74
Enbrel TNFR 2-Ig Psoriasis, RA 15
Rituximab Anti-CD20
NHL
CLL
SLE
0
26
Humira Fully human anti-TNFα RA 12
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Unwanted Immunogenicity
Proteins Patients
Alter
PK/PD
Neutralize biologic
effects and compromise
further therapy (factor
VIII, IFNa2a, GM-CSF)
Cross-react with native
protein and induce adverse
symptoms (Epo, MGDF)
Non immunogenic
(G-CSF, IFN-g)
No effect
(growth hormone,
insulin)Immunogenic
(induce antibodies)
Potential Clinical Consequences of Immunogenicity
• Benign, non-significant to serious, life-threatening depending
on the therapeutic
– Efficacy—reduction of the clinical response
– Safety—safety issues can occur even when there is no
loss of efficacy
• Acute consequences
– Infusion reactions, anaphylactic reactions
• Non-acute consequences
– Delayed-type hypersensitivity/immune complexes
– Cross-reactivity with an endogenous counterpart
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Factors Influencing Immunogenicity Product & treatment related
• Protein (structure, primary sequence, novel epitopes,
glycosylation, oxidation, deamidation)
• Product impurities, formulation, aggregation, degradation,
• Properties of the protein eg, immunostimulatory,
replacement therapy, physiologically important?
• Dose, route, frequency of administration and duration of
therapy
Patient related
• Age, gender, genetic make-up, ethnic sensitivity (IFN-α2a
more immunogenic in Chinese vs Caucasian hepatitis
patients 39% vs 14%), immune status, disease
Production Process Complex manufacturing process
− Expression system/vector− Fermentation/ cell culture process− Purification process− Formulation and filling − Drug Product
New manufacturer (copy product)
−Manufacturing and/or purification
process different, no access to know-
how of the process/history of product;
limited to public domain information
Step-Wise Process
Changes
Product likely to have
altered characteristics
Carson KL, Nat Biotechnol. 2005; 23 (9):1045-1048.
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Complexity of Proteins
Biosimilars in the EU
Comparability studies are needed to demonstrate the
similar nature, in terms of quality, safety and efficacy,
of the new similar biological medicinal product and the
reference product authorized in the EU
Emphasis has been given to immunogenicity
Any subtle change introduced in the manufacturing
process of a given product can have enormous
implications for immunogenicity
Unwanted ImmunogenicityCurrent Position
Testing for unwanted immunogenicity is integral to product
development (clinical & post-marketing phase) for ensuring:
– Clinical safety of a biotherapeutic
– Product comparability
– When a biosimilar product is developed
EMA Guidance
• Guideline on Immunogenicity Assessment of Biotechnology-
Derived Therapeutic Proteins EMA/CHMP/BMWP/14327/2006
• Guideline on Immunogenicity Assessment of monoclonal
antibodies (in consultation) EMA/CHMP/BMWP/86289/2010
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LMWH
Revised
IFN-a
EMA Guidelines on Biosimilars
mAbs
IFN-b,
FSH
Recent
Consultation
In Preparation
European Medicines Agency. http://www.ema.europa.eu/
Accessed 23 February 2011.
In revision (quality issues)
Unwanted Immunogenicity
• Prediction of immunogenicity– In silico and T cell methods are promising but
information on the true clinical utility of these
approaches in a prospective manner is lacking
• Determination of immunogenicity– Human clinical data needed—cannot be replaced by
use of animal or in vitro or in silico tools
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Unwanted ImmunogenicityThe Most Challenging Issues
• It is impossible to predict
– The incidence of unwanted immunogenicity
– The characteristics of the immune response
– The clinical consequences & significance of
such immunogenicity
• These require assessment in carefully designed
studies
Immunogenicity Testing: A Tiered Approach
Screening assays: for ‘identification’ of all antitherapeutic
binding antibodies
- Enzyme-linked immunosorbent assays (ELISAs): direct, bridging, other formats
- Radioimmunoprecipitation assays (RIPA)
- Surface plasmon resonance (SPR)
- Other technologies
Confirmatory assays: for confirming antibodies
Neutralization assays: for distinguishing neutralizing &
non-neutralizing antibodies.
- Cell-based assay
- Non-cell-based ligand binding assay
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Strategy for Assessment of ImmunogenicityPatient samples taken at appropriate
time-points
Screening Assays-ve samples rejected +ve samples
Confirmatory Assays
Bioassay Confirmed +ve samples Characterization
Assess correlation of characterized antibodies
with clinical responses to biologic therapeutic
Assays for clinical markers and assessment
of clinical response in patients
Immunogenicity Assessment Strategy Design and Interpretation
• Studies need to be carefully and prospectively designed to ensure all procedures are in place prior to initiation
– Selection, assessment, characterization and validation of assays
– Identification of appropriate sampling points, duration of testing
– Sample volumes and sample processing/storage
– Selection of statistical methods for analysis of data
• This applies to all assays as shown in strategy slide
• Strategy needs to be established on a case-by-case basis –product, patients, expected clinical parameters
– In chronic use – sequential sampling for a year
– In view of variability of antibody responses, adequate numbers of patients needed
• However, unwanted immunogenicity may occur at a level, which is not detected in studies pre-approval so assessment post-approval, as part of pharmacovigilance surveillance is needed
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Comparative Immunogenicity
• Studies need to be designed to demonstrate whether the immunogenicity of the products is the same or significantly different
• This may affect the design of the studies & their interpretation
• A homogeneous and clinically relevant patient
population should be selected. Head-to-head studies
using same assays & sampling strategy needed
• The consequences of immunogenicity must also be compared
• Post-approval assessment may be necessary, usually as part of pharmacovigilance surveillance
Immunogenicity of Biosimilars
The immunogenicity of the marketed product does not influence the need for comparative immunogenicity studies
However, if the imunogenicity profiles of marketed and biosimilar products are significantly different, they may be considered DISSIMILAR
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Antibody Frequency for Biosimilars (Presubmission Studies)
Biosimilar Ab Incidence Reference Ab Incidence
Omnitrope (SC) 0/51 (0.0%) Genotropin 1/44 (2.3%)
Valtropin (SC) 3/98 (3.4%) Humatrope 1/49 (2.0%)
Binocrit (IV) 2/314 (0.6%) * Erypo 3/164 (1.8%) *
Silapo (IV)
Silapo (SC)
0/305 (0.0%)
0/323 (0.0%)
Erypo
Erypo
0/304 (0.0%)
0/230 (0.0%)
Ratiograstim (SC) 7/356 (2.0%) Neupogen 2/134 (1.5%)
Zarzio (IV / SC)
(phase 1, crossover)
0% Neupogen 0%
Nivestim 3/183 (1.6%) Neupogen 0/95 (0.0%)
Alpheon (SC) § † 31/111 (27.9%) ** Roferon-A 38/99 (38.4%) **
* Prevalence; ** at end of treatment; § Application refused or withdrawn;
† Assay validation insufficient
Courtesy Martina Weise (Bfarm)
Antibodies and Adverse Effects—EPO
Pure red-cell aplasia (PRCA) and anti-EPO antibodies in patients treated with EPO (EPREX)
• 2002 - 13 cases in chronic renal failure patients, rapid development of severe transfusion dependence within months of therapy, resistant to other EPO products
• Pre 1998 – 2/3 cases
•1998 to June’05 – 260+cases worldwide
Casadevall N, et al. N Engl J Med. 2002;346(7):469-475.
Safety Study for Binocrit Suspended
− No increased immunogenicity from
IV use in patients with renal anaemia
or SC use in cancer patients (both
licensed)
− Postmarketing SC trial in previously
untreated renal anaemia patients: two
cases of neutralizing Ab
Binocrit approved - 2007
Rigorous physico-chemical, biological
characterization & clinical trial data Brockmeyer C, et al. Eur J Hosp Pharm Prac. 2009;15(2):34-40.
>Sixty PRCA cases identified in Thailand. Fourteen EPO products marketed. Link to product(s)?
Cause(s) ?
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Immunogenicity of Other Products
Product Type Disease
Antibody
Incidence %
Remicade Anti-TNFCrohn
RA
61
8
Rituxan Anti-CD20
Non-Hodgkin
SLE
CLL
0
65
Campath Anti-CD52 B-CLL
RA
1.9
29-63
• IFN-β - Incidence of neutralizing antibodies varies –
– Avonex 2% to 6%; Rebif 12% to 28%; Betaferon 25% to 45%
– Loss of efficacy; abs cross-reactive and impact on
disease management and QOL
• Monoclonal antibodies – Ab incidence dependent on product,
disease, age; loss of efficacy noted in some cases.
Immunogenicity Guideline
• Recommendations for routine monitoring of changes in
clinical response and linking immunologic findings to
clinical events
– Immunogenicity as part of all clinical trials (→ indication
specific differences possible)
– Evaluate all patients (… and not in a symptom-driven manner)
– Standardize sampling schedule as much as possible
• Specifically analyse adverse events for linkage to an
unwanted immune response (ie, also in a symptom driven-
manner)
• Provide guidance on how prescriber should handle patient
in case unwanted immune response occurs (increase
dose/discontinue, etc)
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Biosimilars: Unwanted Immunogenicity
Quote from EMA BMWP chairman:
‘Unwanted Immunogenicity is the biggest
challenge for the approval of Biosimilars’