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From preclinical to commercial: The evolution of ADC manufacturing expertise during the last 10 years
The document details the evolution of antibody-drug conjugates (ADCs) and Merck KGaA's journey to becoming a commercial ADC manufacturer over the past decade. It discusses the advancements in ADC technology, including the types of antibodies, linkers, and payloads used, and the global ADC pipeline with numerous clinical and pre-clinical programs. The webinar also highlights the challenges in manufacturing ADCs and the future directions for technology and regulatory considerations.
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Similar to From preclinical to commercial: The evolution of ADC manufacturing expertise during the last 10 years
From preclinical to commercial: The evolution of ADC manufacturing expertise during the last 10 years
- 1. Merck KGaA Darmstadt, Germany JyothiSwamy and Lisa McDermott April 5, 2018 THE 10-YEAR JOURNEY EVOLVING TO A COMMERCIAL ADC MANUFACTURER
- 2. 2 The life sciencebusiness of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada. Webinar: The 10-year Journey evolving to a commercial ADC Manufacturer | April 5, 2018
- 3. Evolution of ADCs Outline Introductionto ADCs A Few Facts about ADCs Chemistry – Then, Now and Next Changes since 2000 Summary Webinar: The 10-year Journey evolving to a commercial ADC Manufacturer | April 5, 20183
- 4. Antibody Payload Linker Specific for a tumor-associated antigen that has restricted expression on normal cells. Designed to kill target cells when internalized and released. Attaches the cytotoxic agent to the antibody. New linker systems are designed to be stable in circulation and release the cytotoxic agent inside targeted cells. Introduction to ADCs Elements of an ADC Conjugation is the step of linking the cytotoxic agent to the antibody. 4 Webinar: The 10-year Journey evolving to a commercial ADC Manufacturer | April 5, 2018
- 5. 2018 & beyond 2017 Global History ADCApprovals 2011 2013 2000/ 2017* MylotargTM Pfizer Adcetris® Seattle Genetics/Takeda Kadcyla® Genentech (Hoffmann LaRoche) BesponsaTM Pfizer Which one is next?** 5 **Experts1 in the field predict that the following to gain approval in the near future a) Sacituzumab govitecan b) Rovalpituzumab tesirine c) Glembatumumab Vedotin d) Mirvetuximab soravtansine *Initially approved in 2000 and withdrawn from US & EU markets in 2010. Based on the new clinical data, FDA re-approved in September 2017 Webinar: The 10-year Journey evolving to a commercial ADC Manufacturer | April 5, 2018 1Beacon reports & alerts and P. Drake & D Rabuka, Bioprocess Online, March 6, 2018
- 6. A Few FactsAbout ADCs 1Beacon Reports and alerts, World ADC Conferences *YTD 6 ADC Pipeline – Globally1 Total Number of Active Clinical Programs Webinar: The 10-year Journey evolving to a commercial ADC Manufacturer | April 5, 2018
- 7. • 4 commerciallyapproved products • ~75 programs in various clinical Phases • >100 pre-clinical programs • 70 to 80% of ADC projects are outsourced for various reasons • No ADC specific guidelines from FDA or EMEA • More clinical trials with combination therapy expected (>200 trials registered) • ADCs beyond Oncology expected to gain prominence: Webinar: The 10-year Journey evolving to a commercial ADC Manufacturer | April 5, 20187 - Anti-infection (Antibody antibiotic conjugate) - Cardiovascular Diseases - Imaging & Diagnostic Agents
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- 9. Testing Flow Material Flow SupplyChain Complexity 9 mAb Production Linker Payload Production Custom Raw Materials (Linker & Payload) Conjugation Bioassay Testing Stability Testing Cold Storage Label, Pack & Clinical Use Formulation & Filling Anywhere from 5-10 CMO’s involved Multi-geographical footprint & logistics
- 10. 10 Available Global ADCTechnologies Cytotoxic Agent• Humanized IgG • Site Specific Engineering • Bi-Specific mAbs • Fab • Engineered NNAA • mAb Fragments • Cleavable • Enzymatic (protease) • Acid Labile (hydrazone) • Non-Cleavable • PEG/Cyclohexyl • Hindered Disulfide • Microtubule Disruption • Maytansines • Auristatins • Auristatin anlogs • Tubulysins • DNA/RNA Damaging Agents • Calicheamicin • Doxorubicin • PBDs • Duocarmycins • Indolinobenzodiaepines • Topoisomerase inhibitor • SN-38 • Amanitin Antibody Linker Webinar: The 10-year Journey evolving to a commercial ADC Manufacturer | April 5, 2018
- 11. 11 ADC History Experience with43 different constructs and >300 batches in Development With Significant emphasis on Chromatographic Purifications Random cysteine or lysine conjugation technology Site directed conjugation via engineered mAbs, enzyme catalyzed or non-natural amino acids Various payloads and Linker chemistries Advances in Analytical Techniques and Regulatory Experience First Full Single Use GMP Manufacture in 2017 Webinar: The 10-year Journey evolving to a commercial ADC Manufacturer | April 5, 2018
- 12. 12 GMP ADC Production #of Batches (g input mAb) 30 - 100 20 101 - 500 54 >500 22 GMP batches 96 ADC Constructs > 25 800 sq.ft Clinical Manufacturing Facility Suite 10,000 sq.ft Commercial Manufacturing Facility Suite Dedicated QA, QC and Regulatory Resources Safebridge Certified Site Our ADC Expertise: Summary ADC Manufacturing Expertise Webinar: The 10-year Journey evolving to a commercial ADC Manufacturer | April 5, 2018
- 13. Lysine Addition HeterogeneousProduct Insufficient Analytical Tools Random Cysteine Loss of Payload due to Retro Michael Addition High DAR species Stability PK/PD Profile Processing Issues Common Issues Purification limited to TFF Technology Built onto mAb platforms vs optimized for conjugation Conjugation Chemistry Then Webinar: The 10-year Journey evolving to a commercial ADC Manufacturer | April 5, 201813
- 14. mAb Advancement • EngineeredCysteine, Non-Natural Amino Acid, Enzyme Mediated • Site Specific conjugation • First Site Specific Conjugate in Clinic -2013 (SGN-CD33A) • Controlled DAR 2 and 4 Species Distribution Stability, Toxicity, Clearance differences • Tighter distribution • Aggregation control • SAR Drug Design Conjugation Chemistry Now and Beyond Webinar: The 10-year Journey evolving to a commercial ADC Manufacturer | April 5, 201814
- 15. Drug Advancement • PayloadMOA • More Potent Cytotoxic Payloads • First PBD Conjugate in Clinic - 2013 Linker Advancement • Modulation of ADC hydrophobicity with hydrophilic Linkers • Optimized on an individual basis General Advancements • Enhanced Analytical tools • Large Scale Chromatography • Technology Customized to ADCs Conjugation Chemistry Now and Beyond Webinar: The 10-year Journey evolving to a commercial ADC Manufacturer | April 5, 201815
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- 17. Antibody Humanized IgG’s • FullLength mAbs • IgG1 >> IgG2 / IgG4 • Random Conjugates Site Specific Conjugates • Engineered Cysteine • Non-Natural Amino Acids • Sequence Tags - Enzyme Mediated - SMARTagTM Platform Antibody Analogs • Bi-Specific mAbs • mAb Fragments Payloads First Generation • Calicheamicin • SN38 • Duocarmycin • Doxorubicin Second Generation • Auristatins • Maytansines Third Generation • PBD’s First Generation • Monovalent • Non-Cleavable • Acid Labile Second Generation • Monovalent • Cleavable – Peptidase • Cleavable - Disulfide Third Generation • Fleximer Platform • Polyvalent • Bio-Degradable Linkers Webinar: The 10-year Journey evolving to a commercial ADC Manufacturer | April 5, 201817 ADC Building Blocks Evolution of Technology / Experience Footprint
- 18. GMP Manufacturing ScaleStaffing Challenges 100-500g / batch Experience or “Fit” Limited Commercial Experience Clinical Supplies Limited Regulatory History Limited High Potent Capabilities Drug Linker Manufacturers Biological Manufactures Modeled after mAb backbone Analytics Process Unit Operations Manufacturing Then Webinar: The 10-year Journey evolving to a commercial ADC Manufacturer | April 5, 2018 18
- 19. Larger scale –1-3Kg/batch Expanded due to multiple trials and combinations Better understanding of pre-clinical models Commercial Experience Regulatory Expectations ie: Species Distribution, Aggregate Control Speed from FIH to Commercial (Breakthrough) CMC on critical path vs Clinical Studies Single-use Technology Complete SU Process Train Disposable UV Flow Paths, on line process monitoring Reduced Cleaning Studies, Reduced Costs 19 Manufacturing Now and Beyond Webinar: The 10-year Journey evolving to a commercial ADC Manufacturer | April 5, 2018
- 20. Process and AnalyticalTechnology (PAT) On line and at line for process understanding Availability of Platform Equipment Semi –Custom Skids for larger scale TFF, Chromatography Distribution Controlled by Chromatography Increase Number of Constructs have Chromatography CHT, SCX, HIC, Mixed Mode 20 Manufacturing Now and Beyond Webinar: The 10-year Journey evolving to a commercial ADC Manufacturer | April 5, 2018
- 21. Single-Use ADC Advancements UpcomingWebinar April 19th: Case Study of Full Single Use Process in GMP
- 22. ADCs: Unique RegulatorySpace Impurities Pre and Post Conjugation Free Drug and Related Species API-like Control of mAb, Linker and Drug Loading and Distribution Free vs Conjugated mAb Unique Stability Profiles Potency Pre and Post Conjugation Controls of Size and Distribution Adapting Analytical Control Strategy to Project Pace Validation per Phase of Development vs Accelerated Path
- 23. Conjugation Chemistrymoving toward Site Specific Constructs Increased toxicity of Payloads Higher diversity of Linkers and Impact on Conjugation, Drugability and Polydispersity Increased Manufacturing Scale Regulatory and Commercial Experience Moving toward Single Use Across all Unit Operations Advancement of Analytical Tools and PAT Implementation of Chromatographic Purification for Distribution Control Acceleration between FIH and Commercial 23 Summary of Manufacturing Changes Webinar: The 10-year Journey evolving to a commercial ADC Manufacturer | April 5, 2018
- 24. 24 • Next Changesin ADCs and the impact on Manufacturing • Increased need for advanced analytical tools and PAT • Implementation of Single Use Reactors • Advances in Chromatographic Purifications and Equipment What’s Next? Webinar: The 10-year Journey evolving to a commercial ADC Manufacturer | April 5, 2018
- 25. Jyothi Swamy jyothi.swamy@sial.com The VibrantM is a trademark of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their respective owners. Detailed information on trademarks is available via publicly accessible resources. © 2018 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved. Lisa McDermott lisa.mcdermott@sial.com