state of the art monoclonal antibody...

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.


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


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


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


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


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


MANUFACTURING EFFICIENCY

STATE OF THE ART 1


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


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


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


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.)


HIGH CONCENTRATION SUBCUTANEOUS FORMULATION

STATE OF THE ART 2


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)


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


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


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


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

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

state of the art monoclonal antibody...

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