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

4

• 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)

8

• 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)

9

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

10

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

12

• Controlling DAR species and residual unconjugated mAb

• Hydrophobic Interaction Chromatography (HIC) Treatment

13

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

14

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)

15

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

25

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