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Manufacturing of Monoclonal antibodies compared to gene/cell therapy -…
Manufacturing of Monoclonal antibodies compared to gene/cell therapy
1. Introduction
1.2 Introduction to Gene/Cell therapy
History
: The FDA approved Kymriah (tisagenlecleucel) first gene therapy in 2017
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Background Information:
The mechanism of gene therapies:
A)
Replacing a disease-causing gene with a healthy copy of the gene
B)
Inactivating a disease-causing gene that is not functioning properly
C)
Introducing a new or modified gene into the body to help treat a disease
Definition:
Involves the transfer of genetic material usually in a carrier or vector with the relevant function and uptake of the gene into the appropriate cells of the body
Potential of Gene/Cell therapy
Numbers of patients who have received effective gene-based therapy is few but has potential to become a game changer in modern therapeutic medicine
Applications:
Cellular immunotherapies, cancer vaccines
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1.3 Manufacturing: An overview of Bioreactors
What is a Bioreactor?
A bioreactor is a stand alone cell culture vessel enabled with sensors and it maintains culture environment
What is cell therapy?
Cell therapy contributes to the largest component of manufacturing time and affects cell product characteristics
What is upstream bioprocessing?
Proteins are produced by cells being genetically engineered to contain the human gene which will express the protein of interest
Advantages of using a bioreactor (in vivo) instead of Ex vivo:
-Reduced manufacturing costs
-Improved process control
-Improved quality
-Improved consistency
What's the difference of manufacturing of mAb compared to gene/cell therapy
mAb easier to manufacture than cell/gene therapy due to cell/gene therapies starting material is patient/donor cells which makes it more complex
1.1 Introduction to Monoclonal Antibodies
Definition:
Man made versions of immune system proteins to aid the humans immune system to fight against the antigen
History:
First approved mAb by US FDA in
1986
OKT3 renamed muromonab-CD3
Background Information:
Initially they were mouse antibodies which were valuable in laboratory and animal research but problematic as therapeutic agents
Potential of mAb:
Estimated market size in 2025 300 billion
Applications:
Therapeutics, Diagnostics, Clinical
2. Monoclonal Antibodies:
2.2 Features for successful Chinese Hamster Ovary cell culture in the bioreactor
Foam prevention
Accurate feeding
High end gassing system
Sterile sampling
Slow and gentle mixing
2.3 Fed batch bioprocessing
What is Fed-Batch bioprocessing?
What's the industry standard?
Today the industry standard for the production of stable proteins such as monoclonal antibodies (mAbs) is a fed-batch process in stirred tank bioreactors of up to 20 kL (Moyle, 2017).
2.1 The use of Chinese Hamster Ovary cells for the production of Monoclonal Antibodies
Definition:
Mammalian cells used to produce a desired protein of interest
History:
isolated from ovary tissue by Theodore Puck in 1957
Facts which prove the reliability of CHO for mAb:
CHO account for 84% of total mAbs produced in cell culture
Advantages:
-Easy to cultivate
-Capable of growing at high cell densities
-Ability to produce diverse, correctly folded and glycosylated proteins
2.4 Continuous bioprocessing
What is Continuous bioprocessing?
What are the drivers for continuous bioprocessing?
Economic (reduced pressure to reduce price of biotherapeutics)
What are the advantages of perfusion process over fed-batch processing?
-Improved quality
-Increased product yield
-Cost savings
3. Gene/Cell Therapy:
3.3 The use of Vectors
What are Vectors?
-Vehicles used to introduce the transgene is known as vectors
What are the types of Vectors?
Viral Vectors
Retrovirus:
-RNA Virus
-One of the best choices for gene therapy as it can integrate DNA efficiently into the host genome.
-Reverse transcription to form DNA
What are the positives of Retrovirus?
-Suitable for ex vivo treatment
-Stable integration
-Infect replication cells
What are the negatives of Retrovirus?
-Provoke immune response
-Adverse effect
-Oncogenic activity
-Uncontrolled integration
-Can not infect non-dividing cells
Adenovirus:
Made up of double stranded DNA
What are the positives?
-Infect both dividing as well as non dividing cells
-Less chance of infection
What are the negatives?
-Provoke strong immune responses
Non Viral Vectors
They are non toxic, non-immunogenic and tissue specific
3.4 Stirred tank Bioreactors
Description of Stirred Tank Bioreactors
What are the advantages/Limitations of using Stirred Tank Bioreactors
Provide an opinion on why or why not this bioreactor is better for the production of Cell/gene therapy
3.2 The use of human cells for Gene/Cell therapy
What is the starting material and why is it highly complex?
Patient and donor cells
What are HEK cells?
E.g.HEK293
Derived from human embryonic kidney cells
Heterogenous mix of cells in the body
What are the Advantages./Difficulties using human cells?
3.5 Single-use Bioreactors
Provide an opinion on why or why not this bioreactor is better for the production of Cell/gene therapy
Description of Single-use Bioreactors
What are the advantages/Limitations of using Single-use Bioreactors
3.1 Gene/Cell therapy and its potential
Gene and cell products are paving the way towards more effective therapeutics for unmet medical needs
Products may be used to modify cells in vivo or transferred to cells ex vivo prior to administration to the recipient
Cancer is the most common disease treated by gene therapy (60%)
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Threat complex diseases and conditions such as cancer, tissue injuries and revolutionary vaccines
4. Manufacturing of Monoclonal Antibodies compared to Gene/Cell therapy
4.1 The difficulties of manufacturing Monoclonal Antibodies and Gene/Cell therapy
What are the difficulties between them and provide own opinion/response to these difficulties
How can these difficulties get in the way of manufacturing or their potential in the future?
4.2 The similarities of manufacturing Monoclonal Antibodies and Gene/Cell therap
y
What are the similarities between them and provide own response/opinion to these similarities
Does the similarities provide potential for gene/cell therapy to become a favoured/dominant form of treatment in the future?
5. Conclusion
5.2 Gene/Cell therapy
Summary of overall research findings and the potential for Gene/cell Therapy
5.3 The future of manufacturing for Monoclonal Antibodies and Gene/Cell therapy
What will the future of mAbs be?
Will the demand for mAbs still be high in years to come?
What will the future be for gene/cell therapy?
5.1 Monoclonal Antibodies
Summary of overall research findings and the potential for mAb's