ANTIBODY DRUG CONJUGATES AND BISPECIFIC ANTIBODIES ... · ANTIBODY DRUG CONJUGATES AND BISPECIFIC...
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ANTIBODY DRUG CONJUGATES AND BISPECIFIC ANTIBODIES: SCIENTIFIC & REGULATORY CHALLENGES AND OPPORTUNITIES
CASSS Midwest Discussion Group
Brian DiPaolo
08 June 2017
Agenda
• Introduction
• Antibody Drug Conjugates
• Bispecific Antibodies
• Conclusion
Introduction
Antibody Drug Conjugates
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• Monoclonal antibodies (mAbs) attached to biologically active drugs by chemical linkers with labile bonds
• By combining the unique targeting of mAbs with the cancer-killing ability of cytotoxic drugs, ADCs allow sensitive discrimination between healthy and diseased tissue
• Recent Examples– Adcetris (2011)
– Kadcyla (2013)
– Besponsa (2017)*
* CHMP Positive Opinion - April 2017
Bispecific Antibodies
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• Combine two or more antigen-recognizing elements into a single construct, able to bind to two or more targets
• This accounts for the fact that more than one pathway is often at the root of disease
• Examples– Blinatumomab - CD19- and CD3-targeting
– Catumaxomab - EpCAM and CD3-targeting
Challenges & Opportunities
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• Manufacturing
• Characterization
• Analytical Control
• Analytical Comparability
• Control Strategies
• Platforms & Combinatorial approaches
Antibody Drug Conjugates
• Monoclonal Antibody• Mechanism of Action
• High / Low Molecular Weight Species
• Viral Safety
• Drug-Linker• Starting Materials
• Stereochemistry
• Impurities
Complexities = Key CMC Considerations (1/2)
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• Conjugated Drug Substance• Control and characterization of drug
load, including residual unconjugated antibody
• Non-proteinaceous impurities
• Cytotoxicity assays in BDS release
• Impact of conjugation on properties and stability of the antibody backbone
Complexities = Key CMC Considerations (2/2)
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mAb
Drug Substance“conjugation”
Drug Linker
Drug Product
Complexities of manufacturing a mAb Safety concerns of manufacturing a highly potent
drug Robust and unique analytical methods for quality
control
A Complex Manufacturing Process
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Manufacturing Challenges
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• Cytotoxicity - Facility and GMP controls– Single use technology
– Dedicated equipment (e.g., based on drug-linker)
– Special considerations (e.g., Brazil)
Manufacturing Challenges
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• Controlling DAR species and residual unconjugated mAb
• Hydrophobic Interaction Chromatography (HIC) Treatment
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Analytical Control - Impurities
• How should limits on small molecule process impurities be established?• Metals, Solvents, Reagents, Byproducts• UF/DF step in manufacturing process? What studies can be used to
support clearance of small molecule impurities?
• To what extent are small molecule impurity limits appropriate for ADCs?• ICH Q3A and Q3B applicability• Molecular Weight of ADC versus impurities• Genotoxic Impurities - advanced cancer indications
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Analytical Control - Impurities
• How should unconjugated mAb be viewed?• Control by manufacturing process• Establish release specification
• Species arising from conjugatable drug-linker impurities• Control at drug-linker specification
• Understanding & identifying impurities
• Specified impurities
• Unspecified impurities (Single Largest Unspecified Impurity)
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Analytical Control - Impurities
• Heterogeneity - DAR species• Control by manufacturing process• Establish release specification
• Average DAR• Quantitative distribution of DAR species
• To what extent should heterogeneity be seen as a problem that needs to be overcome?• Safety, PK, activity data of individual DAR species and unconjugated
mAb
Analytical Control - Methods
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• Potency– ELISA (early development)
– Cell-based Bioassay
• Purity– Size Exclusion Chromatography (SE-HPLC)
– Hydrophobic Interaction Chromatography (HIC)
– Capillary Gel Electrophoresis (Reduced/Non-Reduced) (CE-SDS)
– Imaged Capillary Isoelectric Focusing (icIEF)
Analytical Comparability (1/2)
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• Changes to mAb manufacturing process– Establish comparability at mAb stage
• Changes to drug-linker process– Equivalency
– Focus on impurity profile
• Changes to drug substance process– Establish comparability at DS and DP
• Changes to drug product process– Establish comparability at DP
Analytical Comparability (2/2)
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• Principles of ICH Q5E apply
• Considerations for phase of development
• Tighter acceptance criteria than at release
• In-process controls for critical steps
• Stability
Developing A High Level Control Strategy (1/3)
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• Identify quality attributes
• Analyze for criticality using a risk assessment– Consider impact to patient safety and efficacy
– Without considering prior manufacturing history, specific process controls, process characterization studies, or process knowledge
Developing A High Level Control Strategy (2/3)
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• Each component has the potential to impact a subset of the quality attributes of the ADC
• Some quality attributes may be affected in multiple stages of manufacturing, while others may be impacted by a single stage
• Some attributes may be difficult to measure in the final drug product, so these attributes may need to be monitored and controlled at an intermediate stage of manufacture
Developing A High Level Control Strategy (3/3)
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Platforms & Combinatorial Approaches
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• Speed to the Clinic– Platform manufacturing processes
– Platform specifications
• Exploring Efficacy & Safety– “Mix & match” approach
– Drug Master Files and cross-referring in US
Bispecific Antibodies
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Manufacturing
Reference Article:Spiess C, Zhai Q, Carter PJ. Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol. Immunol. 2015;67(2 Pt A):95-106
• Largely similar cell growth as mAb-producing cell lines– Variability in growth & productivity, depending on molecule
• Potential impurities include the mono-specific isoforms– Difficult purification
– Impact to yield
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Analytics
• Addressing potency assessments– ELISA binding assays for both domains - early development
– Cell-based assay
• How to characterize the functionality of each component?
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Key Considerations
• Impact of each component on efficacy & safety– Independent
– Additive
– Synergistic
• Immunogenicity
• Special considerations for stability?
Conclusions
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Conclusions
• Challenges & Opportunities across ADC’s and Bispecific Antibodies– Manufacturing
– Characterization
– Analytical Control
– Analytical Comparability
– Control Strategies
• Potential for speed– Platforms - manufacturing, specifications
– Combinatorial approaches