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How to Accelerate and Enhance ADC Therapies
The webinar discusses services from MilliporeSigma to accelerate antibody-drug conjugate (ADC) development through their ADC Express and ADCore product lines. ADC Express provides integrated antibody, linker, payload, and conjugation services to generate multiple ADC candidates for evaluation. The ADCore product line offers intermediates that simplify payload synthesis and accelerate development timelines. ChetoSensar technology incorporates a chito-oligosaccharide to enhance ADC solubility and efficacy.
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How to Accelerate and Enhance ADC Therapies
- 1. The life sciencebusiness of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada. How to Accelerate and Enhance ADC Therapies Ross Bemowski, Ph.D., Associate Director API R&D Jeff Carroll, Team Lead ADC Express
- 2. The life sciencebusiness of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada
- 3. Agenda 1 2 3 ADC Express™Services Jeff Carroll, Team Lead Chetosensar™ Technology Ross Bemowski, Ph.D. ADCore Payload Intermediates Ross Bemowski, Ph.D.
- 4. 4 Antibody-Drug Conjugate Composition Specificfor 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 and are designed to be stable in circulation and release the cytotoxic agent inside targeted cells. Payloads typically are cytotoxic small molecules Antibody Payload Linker Dolastatins – 40% Maytansinoids – 25% PBD’s – 10% Webinar: How to Accelerate and Enhance ADC Therapies
- 5. Products to accelerateand enhance ADC drug discovery and development Webinar: How to Accelerate and Enhance ADC Therapies 5 ADCore Product Line ChetoSensar™ Technology Discovery/ Pre-Clinical cGMP Clinical Development for Phases 1 and 2 Phase 3 and Commercial ADC Express™ Services Lead Candidate ADC 3 ADC 2 ADC 1 DOLCore™ Intermediate MAYCore™ Intermediate PBDCore™ Intermediate
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- 7. Payloads Used inADC Development 75% of Payloads Arise from 3 Commonly Used Classes Tubulin inhibitors Derived from a sea hare 5 Commercial ADCs Dolastatins Maytansines Tubulin inhibitors Derived from an African shrub 1 Commercial ADC PBD Dimers DNA damaging agents Derived from streptomyces 1 Commercial ADC Webinar: How to Accelerate and Enhance ADC Therapies 7
- 8. 8 Where Do DevelopersGet these Payloads? Purchase commonly used payloads Synthesize novel payloads Clinical / Commercial Research License CDMO Internally develop/manufacture Webinar: How to Accelerate and Enhance ADC Therapies
- 9. Traditional Approach Drug companies mustcurrently: Find a qualified CMO – potent compounds Invest > 5 MEUR per program Invest 2 to 4 years for drug development Invest in ongoing royalty and licensing fees Avoid FTO issues Deal with ongoing supply chain, quality, and regulatory issues Does a more efficient approach exist? 16 Chemical Steps 9 Historic Pathway to Developing Drug Conjugate Payloads Webinar: How to Accelerate and Enhance ADC Therapies
- 10. Solid quality andregulatory platform – DMF/Dossier Supply chain complexity reduced – Flexibility Advantages of the payload core platform include speed to market and FTO - Years 1 2 3 10 Imagine starting a marathon at mile 21… Webinar: How to Accelerate and Enhance ADC Therapies
- 11. ADCore Product Line PBDCore™Intermediate Webinar: How to Accelerate and Enhance ADC Therapies 11 PBDCore™ Intermediate can be used to make diverse and highly potent PBDs Newly launched! Simplify your Payload Synthesis DOLCore™ Intermediate DOLCore™ shortens synthesis of dolastatin payloads to 4 or fewer steps Launched 2021 MAYCore™ Intermediate MAYCore™ can be modified to meet your specific maytansine linker- payload needs Versatility Can be modified to meet your specific linker- payload needs Speed Reduce the number of synthesis steps Reduced- risk Supply chain risk reduction – Ready stock available High Quality Chemical processes optimized to ensure quality Reg. Support Phase appropriate regulatory documents available Royalty-free Royalty-free license Exclusivity Earlier market exclusivity of the commercial drug Saving more patients lives
- 12. DOLCore™ Increases Speedto Clinic and Reduces Risk Traditional Approach Via DOLCore™ Intermediate 16 chemical Steps 3 chemical Steps 12 Webinar: How to Accelerate and Enhance ADC Therapies
- 13. Diversity in yourpayload synthesis PBDCore™ Intermediate: Versatility Your Payload Needs • PBDCore™ intermediate is a versatile product that enables late-stage modifications: - Protecting groups can be selectively cleaved under mild conditions - Ketone (purple) serves as a functional handle for cross-coupling methodologies Versatility PBDCore™ Intermediate Access diverse PBD Payloads Webinar: How to Accelerate and Enhance ADC Therapies 13
- 14. Webinar: How toAccelerate and Enhance ADC Therapies 14 Any linker can be conjugated to MAYCore™ intermediate Low D-ala-MAYCore™ content High diastereopurity maintained in process Key Features MAYCore™ Intermediate MAYCore™ Intermediate: High quality product suitable for all published maytansine linkers Problematic impurity controlled
- 15. 15 Webinar: Howto Accelerate and Enhance ADC Therapies • Only significant conjugatable impurity is D-ala-epimer • Controlled to <2.5 A% in process • Typically, <0.4 A% total other impurities MAYCore™ Intermediate process impurities are well controlled
- 16. Webinar: How toAccelerate and Enhance ADC Therapies 16 ADCore – Accelerating Your Path to the Clinic Synthesis Simplified ADCore products allow for quick procurement of a cGMP supply of your desired drug linker High Quality cGMP Intermediates Highly pure intermediates made through well defined processes Full regulatory support Ready Now! ADCore materials are available now for purchase royalty free Contact us for information about free samples
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- 18. A solution isneeded for the hydrophobicity problem Requires lowering of DAR Subsequent loss of efficacy and smaller therapeutic window Side effects Major modifications needed: Drug-to-antibody ratio (DAR) Change formulation Payload selection Conjugation site Increased use of co-solvent Project termination Additional investments needed (time, $/€, people) Increased development risk Potential IP / FTO restraints Further development ADC poorly soluble Implications Solubility is a technical obstacle for today’s ADC “I am aware of two Small Biotechs that even went bankrupt because they could not solve the solubility issue” - Tier 1 US-based Univ. professor - ~22% of ADC clinical terminations were caused by poor ADC solubility = loss of 2 to 3 programs advancing to commercial, ~15B€ loss over 10 years Webinar: How to Accelerate and Enhance ADC Therapies 18
- 19. Our Chito-oligosaccharide enhancessolubility Consider it Solved! 19 ChetoSensar™ technology is a drug enabler ChetoSensar™ Technology Chito-oligosaccharide Payload (=drug) Antibody Linker Webinar: How to Accelerate and Enhance ADC Therapies 19
- 20. Incorporating ChetoSensar™ technology(CO) into an ADC reduces hydrophobicity 0 5 10 15 20 25 m AU 0 20 40 60 80 100 120 D AD 1 A, Sig=280,4 R e f=o ff (IS18IS018 2018-01-23 08-05-23_H IC 18IS0180000003.D ) 10.631 D AD 1 A, Sig=280,4 R e f=o ff (IS18IS018 2018-01-23 08-05-23_H IC 18IS0180000010.D ) 11.984 13.928 D AD 1 A, Sig=280,4 R e f=o ff (IS18IS018 2018-01-23 08-05-23_H IC 18IS0180000018.D ) 0 5 10 15 20 25 mAU 0 20 40 60 80 100 120 DAD1 A, Sig=280,4 Ref=off (IS18IS018 2018-01-23 08-05-23_HIC18IS0180000003.D) 10.631 DAD1 A, Sig=280,4 Ref=off (IS18IS018 2018-01-23 08-05-23_HIC18IS0180000008.D) 12.168 14.141 DAD1 A, Sig=280,4 Ref=off (IS18IS018 2018-01-23 08-05-23_HIC18IS0180000015.D) Hydrophilic hydrophili c Hydrophobic t/min ADC Absorption Antibody alone ADC + CO Antibody alone CO Webinar: How to Accelerate and Enhance ADC Therapies 20 Hydrophobicity is a key criteria that influences the solubility, permeability and potency of a drug HIC Chromatogram
- 21. Many constructs havebeen prepared Great flexibility with linkers, payloads and antibodies Linkers Disulfide Cat B Maleimide ß-Gluc Payloads Dolastatins Maytansines Duocarmycin CBI Dimers PBD Dimers SN38 Antibodies Various IgG formats Engineered Bispecific Conjugation Technologies Chemical coupling Enzymatic coupling Site specific Stochastic Webinar: How to Accelerate and Enhance ADC Therapies 21
- 22. Chemotherapeutics Maximum tolerated dose(MTD) Minimum effective dose (MED) Maximum tolerated dose Minimum effective dose Traditional ADC ADC with ChetoSensar™ Improved potency no additional side effects Possible fine-tuning -several Payloads possible -different Linker Maximum tolerated dose Minimum effective dose Therapeutic window MTD/MED Drug dose ChetoSensar™ technology broadens the therapeutic window Increased solubility and superior performance for Interchain Maleimide Cat B- MMAE ADC with ChetoSensar™ was seen in in-vivo studies Webinar: How to Accelerate and Enhance ADC Therapies 22
- 23. ChetoSensar™ ADC achievestumor regression close to baseline Efficacy 0 400 800 1200 1600 2000 31 41 51 61 71 81 91 Tumor Volume in mm³ days Vehicle, PBS Only vc-MMAE; DAR 4, 6mg/kg vc-MMAE w/ ChetoSensarTM; DAR 4, 6mg/kg With 1/3 of dose, ChetoSensar™ conjugated ADC gives same result as standard ADC At same dose, ChetoSensar™-ADC led to rapid and complete tumor regression Median results report from a group of 8 mice Key Takeaways Webinar: How to Accelerate and Enhance ADC Therapies 23 SK-OV-3 Xenograph
- 24. ChetoSensar™ achieves tumorregression with proprietary payload 0 200 400 600 800 1000 1200 1400 1600 1800 2000 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 Tumor Volume (mm³) Study Days MKN45 Xenograph No side effects or body weight loss observed with Duocarmycin 8 of 10 animal tumor free, no regrowth observed ChetoSensar™ successfully used in internal R&D projects Key Takeaways Vehicle, PBS 10 mg/kg ADC, without ChetoSensarTM 10 mg/kg ADC, with ChetoSensarTM Webinar: How to Accelerate and Enhance ADC Therapies 24
- 25. • Significantly increaseshydrophilicity of challenging payloads • Can be used with a wide selection of linkers, payloads, and conjugation technologies • Demonstrated increases in efficacy across multiple ADCs Webinar: How to Accelerate and Enhance ADC Therapies 25 ChetoSensar™ Technology: Consider it Dis-solved!
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- 27. Approvals have nearlydoubled the last 3 years Webinar: How to Accelerate and Enhance ADC Therapies 27 The ADC industry 2022 ADC Approval year linker payload Mylotarg 2017;2000 AcBut (lysosome cleavable) Calicheamicin Adcentris 2011 VC Protease cleavable MMAE Kadcyla 2013 Non-cleavable DM1 Besponsa 2017 Hydrazone cleavable Calicheamicin Polivy 2019 VC-PAB cleavable MMAE Padcev 2019 VC-PAB cleavable MMAE Enhertu 2019 Cathepsine cleavable Exatecan (camptothecin) Trodelvy 2020 pH sensitive cleavable, PEG8 camptothecin Blenrep 2020 Non-cleavable MMAF Zynlonta 2021 Cathepsine cleavable PEG8 Tesirine (PBD) Tivdak 2021 VC-PAB cleavable MMAE Noticeable increase in different payloads and linkers
- 28. Webinar: How toAccelerate and Enhance ADC Therapies 28 How can the ADC industry keep accelerating? The Hurdles Optimization of a new ADC requires − developing a mAb that effectively binds to target and manufactures well − choosing the appropriate payload that retains efficacy once delivered − developing linkers that − impart overall in vivo stability − help prevent fast clearance to improve pharmacokinetics − release the payload appropriately at target to retain therapeutic function Each arm has its own challenges when it comes to optimization
- 29. Webinar: How toAccelerate and Enhance ADC Therapies 29 Can we learn from the success of other industries? Small Molecule Medicinal Chemistry R&D thrived in the 90’s when library formats were adopted libraries produced dozens of compounds at a time enabled Structure Activity Relations (SAR) to efficiently identify lead candidates But ADCs are much more complex than small molecules single point, custom modifications around linkers, payloads, and loading require large time and money commitments changing one component of the ADC could influence/alter the behavior of the others making predictions challenging
- 30. Webinar: How toAccelerate and Enhance ADC Therapies 30 How Can ADC ExpressTM Help You With Candidate Selection? 30 mAb1 Lead Candidate ADC3 /4 ADC2 ADC1 GLP & GMP (Development, Clinical & Commercial) Customer Our Company Multiple ADCs Our services for mAb, drug linker, and ADC conjugation development are fully integrated to help accelerate your path to GMP and commercial manufacturing PBDs Camptothecins Auristatins Maytansines Payloads Linkers and Solubility Enhancers noncleavable PEGs cleavable ChetoSensarTM Evaluating more combinations should result in better ADCs
- 31. Understand the payloadto predict which enablers are needed Webinar: How to Accelerate and Enhance ADC Therapies 31 ADC ExpressTM can help with linker selection Our HPLC hydrophobicity screens can help plan for your library needs. We can compare your custom linkers to help predict their behavior as well. Reference Code Compound Class RT RRT vs. Standard A irinotecan 10.161 1.21 B auristatin 10.377 1.24 C maytansinoid 13.248 1.58 D DNA chelator (PBD) 13.928 1.66 E maytansinoid (DM1) 14.107 1.68
- 32. TmAb+Duocarmycin ADC studywith and without solubilizers Webinar: How to Accelerate and Enhance ADC Therapies 32 Hydrophobic characterization of DAR species 0 2 4 6 8 10 12 0 2 4 8 HIC RT (min) Duocarmycin DAR Species Linker Effect on Duocarmycin DAR Species No Enabler Branched PEG 8 Chetosensar Data from Internal ADC Express Trials; J.Ramsay Species evaluation can help predict what DAR target to go after. In this case, the Chetosensar™ DAR 8 shows comparable hydrophobicity to the native mAb.
- 33. Webinar: How toAccelerate and Enhance ADC Therapies 33 TmAb ADCs with varying payloads and linkers Hydrophobic characterization of ADCs 0 2 4 6 8 10 12 Duoc. Cheto-MMAE Cheto-Duoc. Cheto-CBI Dimer PEG8-Duoc HIC RT (min) DAR Species of Various ADC Combinations HIC Screen of DAR Species DAR 4 DAR 8 Data from Internal ADC Express Trials; J. Ramsay HIC profiling can directly evaluate payloads, enablers and DAR
- 34. Ligand ka (1041/Ms)kd (10-4, 1/s) KD (nM) Relative % KD T mAb ADC PEG4 1.22 1.42e 11.6 52.3 T mAb ADC PEG8 0.88 1.05e 11.9 51.0 T mAb ADC PEG12 2.53 1.66e 6.56 92.5 T mAb ADC PEG24 3.06 3.47e 11.3 53.7 T mAb ADC SMCC 2.56 1.69e 6.60 92.0 RS (T mAb) 1.19 0.721 6.07 NA Overall antigen binding activities decreased relative to the unconjugated TmAb PEG 12 and SMCC linker activity had neglectable impact on binding affinity Data indicated linker size influenced the binding activities for different linkers with similar DAR using the same payload Kinetic data including association (ka), dissociation (kd), and equilibrium dissociation constant (KD) allows primarily efficacy data with low sample requirement Surface plasmon resonance (SPR) comparability analysis Understand binding as early as possible 34 Webinar: How to Accelerate and Enhance ADC Therapies
- 35. Work with anexperienced CDMO at the start of your program Webinar: How to Accelerate and Enhance ADC Therapies 35 Where to start building an ADC library ADC Express™ Services can be your partner who − understands and is experienced with various conjugation chemistries − can help design your target ADCs of interest − knows how to get the right pieces in place − can quickly generate the appropriate constructs − has the analytical methods in place to provide reliable characterization for each ADC Why guess at which ADC will be the best? Leverage our expertise to make every ADC of interest and test them Head-to-head!
- 36. Products to Accelerateand Enhance ADC Drug Discovery and Development Webinar: How to Accelerate and Enhance ADC Therapies 36 ADCore Payload Intermediates ChetoSensar™ Technology Discovery/ Pre-Clinical cGMP Clinical Development for Phases 1 and 2 Phase 3 and Commercial ADC Express™ Services Lead Candidate ADC 3 ADC 2 ADC 1 DOLCore™ Intermediate MAYCore™ Intermediate PBDCore™ Intermediate
- 37. Our Vertically IntegratedADC Supply Chain St Louis, MO: ADC Express™ Services ADC Clinical and Commercial development and production Clinical MFG suite expansion complete in 2022 Madison/Verona, WI: Manufacturing site for ADCore products/ChetoSensar™ technology Linker/Payload development through commercial production 65 M € GMP MFG expansion complete 2022 Martillac, France: Cell line development to BDS mAb clinical development and manufacturing Commercial MFG ready in 2022 Sheboygan, WI: Custom non-GMP starting materials Schaffhausen, Switzerland PEG linkers for downstream conjugation Bangalore, India: Custom non-GMP starting materials 37 Webinar: How to Accelerate and Enhance ADC Therapies
- 38. The vibrant M,SAFC, ADC Express, Chetosensar, Dolcore, Maycore and PBDcore are trademarks 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. © 2022 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.