Download Regulatory perspective for successful antibody

Regulatory perspective for successful
antibody-drug conjugate development
Wen Jin Wu, M.D., Ph.D.
Senior Investigator
Division of Biotechnology Review and Research I
Office of Biotechnology Products (OBP)
Office of Pharmaceutical Quality (OPQ)
CDER/FDA
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Disclaimer:
The information presented here reflects the views of the
presenter and does not necessarily represent the views or
policies of the U.S. Food and Drug Administration.
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Schematic structure of antibody-drug
conjugates (ADCs)
mAb
Linker
Drug
mAb
Linkers
Drugs
IgG1, 2 or 4
1. Cleavable
• peptide
• disulfide
• acid-labile
hydrazone
2. Non-cleavable
• thioether
1. Tubulin inhibitors
• maytansinoides
• auristatins
2. DNA damaging agents
• Calicheamicin
• PBD dimer
• duocarmycins
3. Topoisomerase inhibitor
• SN-38
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Milestones: FDA approved ADCs
IND submission
1993
FDA approval
7 years
2000
Gemtuzumab ozogamicin (Mylotarg)
(accelerated approval)
(withdrawn in 2010)
2006
6 years
2011
Brentuximab vedotin (Adcetris)
(accelerated approval )
2005
8 years
2013
Ado-trastuzumab emtansine (Kadcyla)
(T-DM1)
Hydrazone Calicheamicin
Anti-CD33
(humanized IgG4)
S
Anti-CD30
(Chimeric IgG1)
Peptide
MMAE
N
Anti-HER2
(Humanized IgG1)
Thioether
DM1
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ADC success depends on optimization
of each component
Monoclonal antibody/target
• Target specificity (tumor)
o Drug delivery
• Target binding affinity
o Unaltered compared to naked mAb
• Internalization
o Rapid process
• Target expression
o High on tumor cell surface, low in normal tissues
Source:
Chari RV. Accounts of Chemical Research, 2008;41:98-107
Teicher BA. Current Cancer Drug Targets, 2009;9:982-1004
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ADC success depends on optimization of each
component– cont.
Linker
• Stable in plasma and labile in target cells to
release drug in the active form
• Stable upon storage
Drug
• High potency
• Linkable
• Water soluble
• Validated mechanism of action
Source:
Chari RV. Accounts of Chemical Research, 2008;41:98-107
Teicher BA. Current Cancer Drug Targets, 2009;9:982-1004
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Mechanisms of action of ADC
1) Internalization of the ADC complex
and drug release following binding to
antigen
2) Antibody-associated mechanisms
 ADCC
 CDC
 Signaling pathways
Example: T-DM1, where antibody has
demonstrated clinical activity
3) Bystander effect
 The ability of an ADC to produce cytotoxic effects on antigen positive, as well as
on antigen-negative cells upon processing and releasing of the metabolized
payload into the tumor microenvironment
Example: brentuximab vedotin, which is capable of killing both CD30-positive and
CD30-negative cells
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Increasing ADC IND submissions at FDA
Number of ADC INDs
50
40
30
20
10
0
Note: In 2015, 8 ADC INDs and 5 ADC pre-INDs were submitted to FDA.
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Number of antigens
targeted by ADCs
Target selections
Antigen targeting
frequency by ADC(s)
There is a minimal overlap of antigens targeted by different ADCs
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“ADCs are giving new life to targets”
(Mullard A. Nature Review: Drug discovery. 2013:329-332.)
mAb-mediated internalization demonstrates the usefulness of the
targets as a guidance system for payloads even though the naked
mAbs themselves fail to sufficiently kill cancer cells or become
resistant by tumor.
Relapsed or refractory Hodgkin’s Lymphoma
No. of patients
Dose
The rate for the
objective responses
Brentuximab vedotin
SGN-30
(anti-CD30 ADC)
(a chimeric anti-CD30 mAb)
102
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1.8 mg/kg
6 or 12 mg/kg
75%
0%
(Forero-Torres et al. British Journal of Hematology, 2009:146;171–179; Younes et al. Journal of Clinical Oncology, 2012:30:2183-2189)
T-DM1 targets HER2 again to treat trastuzumab-resistant
disease.
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Number of ADCs
Number of ADCs
ADC component: monoclonal antibodies
60
50
40
30
20
10
0
IgG1
IgG2
IgG4
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Number of products
ADC component: linkers
40
35
30
25
20
15
10
5
0
Uncleavable
thioether based
Disulfide based
Enzyme cleavable
dipeptides
Acid labile
• Fewer products contain relatively unstable linkers with short half-lives
such as disulfide-based linkers and hydrazones
• More products use linkers with improved stability in systemic
circulation, e.g., peptide and non-cleavable thioether linkers
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 Cysteine or lysine
 These random conjugation processes produce
heterogeneous ADC products with different drug load
distribution and drug/antibody ratio (DAR)
 Heterogeneity in overall charge of lysine conjugates can
impact solubility, stability, and pharmacokinetics
 The conjugation process should be well controlled to
ensure the lot-to-lot consistency
 Site-specific
 The site-specific conjugated ADCs have displayed
homogeneous labeling
1) Engineered cysteines
2) Insertion of an “unnatural” amino acid
3) Bacterial transglutaminase
Number of products
ADC conjugation sites
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Number of products
ADC component: payloads
45
40
35
30
25
20
15
10
5
0
Traditional
chemotherapies
Enzyme
targeting agents
More ADCs are
armed with
microtubule
inhibitors.
DNA targeting
agents
Microtubule
targeting agents
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Regulatory requirements of ADCs
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ADC regulation
• There is no specific Regulatory Guidance to Industry on ADC development
• FDA follows existing guidelines for small drugs and monoclonal antibodies
to regulate ADC
• ADC review is a collaborative effort across product quality offices at FDA:
o Office of Biotechnology Products (OBP)/OPQ primarily focuses on the
manufacturing of the antibody component of the ADC and the control
strategy for the antibody intermediate, as well as for the drug substance (DS)
and drug product (DP)
o Small molecule review groups in OPQ bear primary responsibility for review of
the adequacy of the payload and linker, conjugation reaction and aspects of
the control strategy
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Characterization of mAb intermediate and ADC
mAb intermediate
Primary structure amino acid (aa) composition, N-terminal/C-
ADC-specific
drug attachment sites
terminal sequence analysis, peptide mapping
Conformational
structure
Posttranslational
modifications
size and charge variants, molecular weight
Impurities
product-related Impurities, e.g., dimers,
aggregates and degradation products
Biological activity
•
•
drug load distribution and
drug/antibody ratio (DAR)
e.g., sialic acid determination, monosaccharide
content and oligosaccharide profile analysis
free drug and its related
substance, residual solvents,
heavy metals and
unconjugated mAb
process-related Impurities, e.g., microbial
contaminants, HCP, host cell DNA
target specific binding and binding affinity, and cytotoxicity
effector function
The expectations for the characterization of unconjugated mAb are the same whether
or not it will be developed on its own or as part of an ADC
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Conjugation may impact on mAb: 1) binding affinity and effector function, 2) primary
structure and posttranslational modifications , 3) size and charge variants.
ADC DS and/or DP release specifications
•
•
•
•
Appearance, pH, osmolality, total
protein
Identity
– binding
– charge based
– peptide mapping
Impurities – drug
– free drug and its related
substances
– residual solvents
– heavy metals
Drug/antibody ratio
•
•
•
•
Purity/Impurities – mAb
– monomer, fragments and
aggregates
– charge variants
– unconjugated antibody
Particulate matter (USP<788>)
Safety
– Endotoxin
– bioburden/sterility
Potency
– Binding
– cytotoxicity assay
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Drug/antibody ratio (DAR)
and
drug load distribution
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DAR and drug load distribution (cysteine-linked ADC)
Fig. 2 A representative HIC chromatogram
(Ouyang J. Antibody-Drug Conjugates, Methods Mol Biol 2013;1045:275-83.)
1. The hydrophobic interaction chromatography (HIC) method has been developed
to determine the drug load distribution and DAR for cysteine-linked ADCs
2. Based on the drug load profiles, drug load distribution and DAR can be
calculated
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DAR and drug load distribution (lysine-linked ADC)
(Basa L. Antibody-Drug Conjugate, Methods Mol Biol 2013;1045:285-293.)
1. MS-based method has been developed to determine the DAR and drug load distribution
for lysine-linked ADCs
2. Drug load distribution (%) = (peak area of Ab with drug load n/sum of all peak areas x
100 (%) (n is number of drug load)
3. DAR = Ʃ (drug load distribution (%) of each Ab with drug load n (n)/100
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Sites of attachment
1. Well controlled and robust chemical process leads to reproducible product
2. Peptide map ‘fingerprint’ of drug-containing peptides shows consistency
between processes at different scales and sites
3. Lot-to-lot the same lysines are modified at the same % occupancy
(Fred Jacobson, CASSS CMC Strategy Forum Japan 2013) (Courtesy of Dr. Fred Jacobson)
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DAR and drug load distribution:
 They are critical product quality attributes
 They determine the drug quantity to which the patient is exposed
 Various drug-loaded forms may differ in their PK/PD characteristics
(Basa L. Antibody-Drug Conjugates, Methods Mol Biol 2013;1045:285-293)
Question:
Should “Drug load distribution” be included in
the lot release specifications for a better
quality control on ADCs?
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ADC stability
• DS and DP stability studies
–
–
–
–
Stability testing methods and acceptance criteria
Test time/intervals
Storage conditions: long term, accelerated and stressed
Stability indicating assays
• ADC serum stability
– Linker stability
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Issues identified in pre-IND meeting packages
1. The sponsor considered the small molecule of ADC as DS
- The small molecule potion of ADC is considered as an intermediate, and
antibody conjugated with small molecule via a linker is considered DS.
2. The mAb potion of ADC was functioning to target cancer cells and was not
considered as an active molecule in the ADC. Therefore, the sponsor thought
the antibody component would not need further CMC characterization
- The mAb is a component of the mechanism of action of ADC. The
expectations for characterization of the mAb intermediate are the same
whether the mAb is used alone or as part of a conjugated structure.
3. The sponsor proposed to use “non-GMP DM1 reagent” in the GMP
manufacturing of preclinical and clinical lots of ADC
- DM1 is not a reagent. It is a drug substance intermediate. Therefore, DM1
should be manufactured under GMP.
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Toxicology lots vs. lots to be used in the Phase 1
clinical study
Issues: The toxicology lot and the clinical lot were manufactured by different
processes. The original IND submission lacked sufficient data to demonstrate
comparability of the toxicology and clinical lots.
General considerations for monoclonal antibody products:
1.One lot each of the toxicology and clinical product may be sufficient to assess comparability at this
stage of drug development
2.The focus of the comparability exercise is usually on an evaluation of quality attributes related to
safety, such as impurities
3.The potency of the product should be considered in the comparability assessment
4.Generally, the phase I clinical product should have comparable or improved quality attributes (e.g.,
improved purity) relative to the toxicology product
5.Comparative stability data (real-time, accelerated, stress or forced degradation stability) are
generally not required to demonstrate comparability of the non-clinical and phase I clinical products
•
In the case of ADCs, comparability evaluation is focused on product impurities
profiles, DAR and potency. Comparable DARs should be maintained between the
toxicology lot and the clinical lot.
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Example:
Pitfalls encountered in setting DS and DP lot release
specifications and stability study
Potency assays:
1. Cytotoxicity assay or binding assay was not included as part of DS or DP lot
release specifications.
– Both binding and cytotoxicity assays should be included for ADC lot
release and stability study.
2. Potency of the DS was to be measured with an binding assay while the DP
potency was determined using a cytotoxicity assay.
– It is recommended that a relevant potency assay, such as the cellbased cytotoxicity assay proposed to be used for DP testing, be
incorporated into the DS release and stability testing program.
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Example:
Pitfalls in setting DS and DP lot release specifications
and stability study – cont.
Potency assays:
3. The proposed specifications for DS and DP lot release for the antigen
binding and the cytotoxicity assay were unusually broad, e.g., 50-200% of
reference standard.
– This may not provide sufficient control over product potency to ensure
consistent dosing. Furthermore, antibody-drug conjugates generally
have a narrower therapeutic window than naked mAbs due to their
higher toxicity. Provide scientific justification for the values proposed.
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Example:
Pitfalls in setting DS and DP release specification and
stability study – cont.
Charge variants:
• An assay to monitor charge isoforms was not included as part of DS and
DP lot release and stability studies.
– A charge assay with quantitative acceptance criteria should be
incorporated into DS and DP lot release specifications and stability
study.
– Until quantitative acceptance criteria can be established, a semiquantitative criterion such as “conforms to reference standard” with a
well-defined conformance description can be used. However, the
quantitative results should still be reported at release and on stability.
Caveat: Charge based assays may not be possible/meaningful after
conjugation to lysine residues.
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Example:
Pitfalls in setting DS and DP release
specifications and stability study – cont.
• Unconjugated antibody testing was not included as part of DS and DP lot
release
• Numerical acceptance criteria for unconjugated antibody were not set for
lot release
• Quantitative acceptance criteria for DAR were not included for the release
and stability study
• The acceptance criteria for free drug and its related species were not
appropriately set
– Tighten your proposed acceptance criteria for free drug in the DS and
DP specifications based on your actual manufacturing batch test data
and provide the justifications for the acceptance criteria for the free
drug species.
– For Phase 1, free drug related impurities in clinical lot should be
qualified relative to data from toxicology studies.
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Summary
• ADCs are a rapidly growing area in drug
development, as reflected by a significant
increase in IND submissions to the FDA.
• Advances in technology have optimized
ADC development.
• Early communication with FDA regarding
regulatory strategy is advisable.
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Acknowledgement
• OBP
 Milos Dokmanovic
 Haoheng Yan
 Wendy Weinberg
 Marjorie Shapiro
 Kathleen Clouse
• ONDP
 Xiao-Hong Chen
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