ANTIBODY DRUG CONJUGATES AND BISPECIFIC ANTIBODIES: SCIENTIFIC & REGULATORY CHALLENGES AND OPPORTUNITIES

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1 ANTIBODY DRUG CONJUGATES AND BISPECIFIC ANTIBODIES: SCIENTIFIC & REGULATORY CHALLENGES AND OPPORTUNITIES Brian DiPaolo 08 June 2017 CASSS Midwest Discussion Group

2 Agenda Introduction Antibody Drug Conjugates Bispecific Antibodies Conclusion

3 Introduction

4 Antibody Drug Conjugates Monoclonal antibodies (mabs) attached to biologically active drugs by chemical linkers with labile bonds By combining the unique targeting of mabs with the cancerkilling 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

5 Bispecific Antibodies 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 5

6 Challenges & Opportunities Manufacturing Characterization Analytical Control Analytical Comparability Control Strategies Platforms & Combinatorial approaches 6

7 Antibody Drug Conjugates

8 Complexities = Key CMC Considerations (1/2) Monoclonal Antibody Mechanism of Action High / Low Molecular Weight Species Viral Safety Drug-Linker Starting Materials Stereochemistry Impurities 8

9 Complexities = Key CMC Considerations (2/2) 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 9

10 A Complex Manufacturing Process Complexities of manufacturing a mab Safety concerns of manufacturing a highly potent drug Robust and unique analytical methods for quality control mab Drug Substance conjugation Drug Product Drug Linker 10

11 Manufacturing Challenges Cytotoxicity - Facility and GMP controls Single use technology Dedicated equipment (e.g., based on drug-linker) Special considerations (e.g., Brazil) 11

12 Manufacturing Challenges Controlling DAR species and residual unconjugated mab Hydrophobic Interaction Chromatography (HIC) Treatment 12

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 13

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) 14

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 15

16 Analytical Control - Methods 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) 16

17 Analytical Comparability (1/2) 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 17

18 Analytical Comparability (2/2) Principles of ICH Q5E apply Considerations for phase of development Tighter acceptance criteria than at release In-process controls for critical steps Stability 18

19 Developing A High Level Control Strategy (1/3) 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 19

20 Developing A High Level Control Strategy (2/3) 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 20

21 Developing A High Level Control Strategy (3/3) 21

22 Platforms & Combinatorial Approaches Speed to the Clinic Platform manufacturing processes Platform specifications Exploring Efficacy & Safety Mix & match approach Drug Master Files and cross-referring in US 22

23 Bispecific Antibodies

24 Manufacturing 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 Reference Article: Spiess C, Zhai Q, Carter PJ. Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol. Immunol. 2015;67(2 Pt A):

25 Analytics Addressing potency assessments ELISA binding assays for both domains - early development Cell-based assay How to characterize the functionality of each component? 25

26 Key Considerations Impact of each component on efficacy & safety Independent Additive Synergistic Immunogenicity Special considerations for stability? 26

27 Conclusions

28 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 28

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