state of the art monoclonal antibody...
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Copyright 2013-2016 Songpon Deechongkit for Educational Purpose only
State of the Art Monoclonal Antibody Development
For THAITECT 2016, Bangkok Thailand Session III: Phase I&II Vaccine and Monoclonal Antibody Designs and Advancement Criteria
Songpon Deechongkit, Ph.D. Managing Director
Siam Bioscience Co., Ltd.
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Copyright 2013-2016 Songpon Deechongkit for Educational Purpose only
There Are Four Major Groups of Biopharmaceuticals
Endogenous Proteins
Biotech-derived
Monoclonal antibodies (mAbs) and Fc-Fusion Proteins
Biotech-derived
Synthetic Peptides & Peptidomimetics Chemically-derived
Antibody-Drug Conjugates (ADCs)
Mixed Modality
Development History Timeline
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Copyright 2013-2016 Songpon Deechongkit for Educational Purpose only
Therapeutic Monoclonal Antibodies in The Market Are Diverse
Different subtypes Different degrees of humanization
Mouse CDRs
Murine antibody
Human antibody
Source: http://www.fusionantibodies.com/index.cfm/area/information/page/monoclonalantibodies
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Copyright 2013-2016 Songpon Deechongkit for Educational Purpose only
Therapeutic Monoclonal Antibodies in The Market Are Diverse
Different Fragments Different modifications
Source: Advances in Bioscience and Biotechnology Vol.4 No.5(2013) http://www.gene.com/stories/understanding-antibody-drug-conjugates http://www.cimziahcp.com/psoriatic-arthritis/cimzia-design
Antibody-drug conjugates
Pegylations
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Copyright 2013-2016 Songpon Deechongkit for Educational Purpose only
Overview: Original mAb Development Pathway
Discovery Screen Hit to Lead
Lead Opti-mization Pre-Clinical Phase I Phase 2 Phase 3 Filing Launch
Phase 4 Post Launch
Therapeutic Disease Assessment
Lead Selection & Pre-clinical Testing
Product Development Market Readiness Regulatory Approval
Launch
Target Selection
Molecule Selection
Produce Toxicology & Clinical Reagents
Pre-Clinical Pharmacology Toxicology Studies
Develop Marketing Strategies
Sales Force Training Development and Launch
Implement Regulatory Filings and Strategies
Clinical Safety, Biological Activity and Efficacy
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Copyright 2013-2016 Songpon Deechongkit for Educational Purpose only
Overview: Biosimilar mAb Development Pathway
Molecule, Process, and Analytical Development Pre-Clinical Phase I Phase 2 Phase 3 Filing Launch Phase 4
Post Launch
Develop and Ready for Characterization Product Development (Reduced Scope) Market Readiness
Regulatory Approval Launch
Project Selection
Chemistry Manufacturing & Control (CMC) Section Development
Produce Toxicology & Clinical Reagents
Pre-Clinical Pharmacology Toxicology Studies
Develop Marketing Strategies
Sales Force Training Development and Launch
Implement Regulatory Filings and Strategies
Clinical Safety, Biological Activity and Efficacy
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Copyright 2013-2016 Songpon Deechongkit for Educational Purpose only
MANUFACTURING EFFICIENCY
STATE OF THE ART 1
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Copyright 2013-2016 Songpon Deechongkit for Educational Purpose only
Gene synthesis for target protein
Insert gene into expression vector
Most mAbs Are Produced by Mammalian Cells
Transient expression
e.g. Chinese hamster ovary cells
Insert vector into cells
Stable expression
Gene amplification
Select high producer cell line -> top 2%
Limiting dilution Obtain stable cell line
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Copyright 2013-2016 Songpon Deechongkit for Educational Purpose only
Typical process utilized for monoclonal antibody production
Source: Rathore, A. S. Follow-on protein products: scientific issues, developments and challenges. Cell 27 (12) 698-705 (2009).
Upstream Processing
Downstream Processing
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Copyright 2013-2016 Songpon Deechongkit for Educational Purpose only
Source: Chartrain M., Lily C. Current Pharmaceutical Biotechnology 9(6) 447 467 (2008).
Monoclonal Antibodies Upstream Process Can Vary
Batch: Good with small scale, not
practical for commercial scale
Fed-Batch: High cell density Long process time before harvest Require large tank and large
facility
Perfusion: High cell density Long process time with
continuous harvest Medium size tank and facility
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Copyright 2013-2016 Songpon Deechongkit for Educational Purpose only
Trends: High Cell Density Perfusion
Standard Technology: Big Tanks
Fed-batch; 20,000 L tanks High cost / mg
Current & Future Trend: Small tank and Single use
High cell density perfusion in single use Bioreactor; 2,000 L bag, same or better Yield than fed-batch
Source: Bioengineering AG (Switzerland) and GE (U.S.A.)
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Copyright 2013-2016 Songpon Deechongkit for Educational Purpose only
HIGH CONCENTRATION SUBCUTANEOUS FORMULATION
STATE OF THE ART 2
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Copyright 2013-2016 Songpon Deechongkit for Educational Purpose only
Liquid formulations
Lyophilized (freeze-dried) formulations Need to be reconstituted with water-for-injection (WFI) before use
Major Types of Biopharmaceutical Formulations
Vial Pre-filled syringe (PFS)
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Copyright 2013-2016 Songpon Deechongkit for Educational Purpose only
Protein Formulation
Antimicrobial Agent
Benzyl Alcohol
Buffering Agent
Acetate, Phosphate
Non-ionic surfactant
Polysorbate 20 Polysorbate 80
Tonicity Modifier
NaCl Sorbitol Lyoprotectant
Sucrose Trehalose
Arginine
Bulking Agent
Mannitol Glycine
Antioxidant Ascorbate Methionine
CryoProtectant Sucrose Sorbitol Glycine
Typical Components in a Protein Formulation
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Copyright 2013-2016 Songpon Deechongkit for Educational Purpose only
Patient Demands: Subcutaneous delivery instead of IV infusion
Example 1: Herceptin From: lyophilized IV formulation To: 120 mg/mL subcutaneous formulation
Example 2: Mabthera From: liquid 10 mg/mL IV formulation To: 120 mg/mL subcutaneous formulation
Source: MIMS
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Copyright 2013-2016 Songpon Deechongkit for Educational Purpose only
Other Trends and Considerations in mAb Development
Non-Clinical Studies: Applying 3Rs concept o 3Rs = Replace, Refine, Reduce o In the end, non-human primates are required for non-clinical studies o Trends:
Development of in vitro model For biosimilar mAbs, in vitro becomes much more essential than in vivo
studies
Clinical Studies: Addressing immunogenicity o If possible, design out questionable sequences based on in silico prediction and
bioinformatics o Animal data are NOT predictive of immunogenicity o Immunogenicity is always a case-by-case basis consideration o NO one-size fits all approach
Source: WHO-MFDS workshop 2014
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Copyright 2013-2016 Songpon Deechongkit for Educational Purpose only
Summary State of the Art Monoclonal Antibody Development
Always plan with the end game in mind
Price competition leads to optimization of production efficiency
Patient demands necessitate launch of product in high concentration subcutaneous formulations
Due to the encouragement of 3Rs principle, non-clinical studies will become more focused on in vitro studies than in vivo studies, particularly for biosimilars
It is important to address immunogenicity early, especially for new mAbs, which can be achieved by in silico prediction and bioinformatics
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Thank you
World-class Manufacturing, Enabling Better Healthcare
www.siambioscience.com
Slide Number 1There Are Four Major Groups of Biopharmaceuticals Therapeutic Monoclonal Antibodies in The Market Are DiverseTherapeutic Monoclonal Antibodies in The Market Are DiverseOverview:Original mAb Development PathwayOverview:Biosimilar mAb Development PathwayManufacturing EfficiencySlide Number 8Typical process utilized for monoclonal antibody productionMonoclonal Antibodies Upstream Process Can VaryTrends: High Cell Density PerfusionHigh Concentration Subcutaneous FormulationMajor Types of Biopharmaceutical FormulationsSlide Number 14Patient Demands: Subcutaneous delivery instead of IV infusionOther Trends and Considerations in mAb DevelopmentSummary State of the Art Monoclonal Antibody DevelopmentSlide Number 18