Samenvatting
Summary Biopharmaceuticals and biopharma proteomics (XM_0108)
- Instelling
- Vrije Universiteit Amsterdam (VU)
This document consists a summary of all lectures
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Lecture 1. Biopharmaceutical typesBiotechnology
Biotechnology encompasses any technique that uses living organisms in the
production or modification of products
- Thus it products broadly refer to biopharmaceutical drugs generated
through researches in cell biology, genetics and recombinant DNA
technology
o Recombinant DNA (rDNA) and monoclonal antibodies ( MAb ) are
providing exciting opportunities for new pharmaceuticals
development as well as new approaches to drug delivery
What are Biotech Medicines?
Biotech medicines often replace or supplement a natural protein produced by
the body, satisfying medical needs previously unmet by chemical medicines.
What are biopharmaceuticals?
- Definition is disputed
o (In the broadest interpretation). Therapeutic agents from natural sources
o Overlaps, for example, with Gene Therapy and small molecule natural
products
- There are several competing terms, such as biologicals, biological products
and biological medicinal products which are defined, for example by
regulatory authorities
- We focus on the most common group peptide and protein
biopharmaceuticals
- So biopharmaceuticals are
o Protein or nucleic acid based pharmaceutical therapeutics (most
important)
o High molecular weight drugs produced using recombinant DNA
technologies
o Produced by means other than:
1. Direct extraction from a biological source
2. Or chemical synthesis
- Some examples: Recombinant protein Insulin from E.coli; Antisense DNA
blocks protein production; Monoclonal Antibody to work with immune
system
Biopharmaceuticals VS conventional drugs
Small molecule drug Biopharmaceutical
Size Small (< 1500 Da) Large (> 3000 Da)
Structure Simple, well defined; Complex; may be heterogeneous;
independent of manufacturing strongly depends on manufacturing
process process
Modifications No or few; well defined Many possibilities
Manufacturin Produced by chemical Produced in living cell culture
g synthesis - Difficult to control from starting
- predictable chemical material to final API
process - Impossible to ensure identical
- identical copies can be copy
made
Stability High; well defined Unstable; sensitive to external
conditions
Characterizat Easy to characterize Can’t be characterized completely
ion completely due to molecular composition and
heterogeneity
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,Immunogenic Mostly non immunogenic Ability to generate a significant
ity immune response
Cost for use <1$ per day >20$ per day
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,Biopharmaceuticals tend to have high efficacy and less off target specificity and
are more diverse than small molecule drugs.
Biopharmaceuticals tend to have less side affects and toxicity (when it comes to
chemical toxicities such as carcinogenicity and/or teratogenicity).
Biopharmaceuticals must apply different safety regulations; Biocompatibility and
Biodegradability + Immunologically safe.
Biopharmaceuticals = biomolecules?
- Biopharmaceuticals are not only small molecules, but also:
o Lipids (phospholipids, glycolipids, sterols), vitamins, hormones,
neurotransmitters
o Carbohydrates (glucose, disaccharides), amino acids, nucleotides,
peptides, oligopeptides, proteins, nucleic acid (DNA, RNA)
o Polysaccharides (heparin)
New Biological Entity (NBE)
- Biological product, substance or medicinal product
- Biologic, Biotech or Biochemical product
- Made by cells
o Chemically modified protein
o Fusion protein
o (heterogeneous mixture of) e.g. PEGylated protein
o Mab
- (Partly) via rDNA generated product
- May include chemical synthetic steps
- (Partly) produced with the use of living organisms
- Product may contain (additionally) process related impurities (e.g. DNA, host
cell proteins, viruses)
- Production environment is more stringent (e.g. restrictions regarding use of
living organisms)
- Complex pharmaceutical ingredient
o NBE’s require more (diverse) analytical techniques
o Impurity, drug related substance and DS may be undistinguishable
o “Case by case” approach for each (sub --)class, production or purification
method
- Whole process is the key point!
New Chemical Entity (NCE)
- Chemistry, synthesis (key point)
- E.g. synthetic polypeptide/ biological
- Completely synthetic, without use ( eucaryotic, procaryotic ) living organisms
- The product contains predominantly product related impurities
Characteristic discriminators NCE vs NBE
- Molecular size and complexity
o But what about synthetic (pseudo) peptides?
o Secondary and tertiary structural elements
- Heterogeneity, e.g. glyco proteins (recombinant FSH)
- Production and purification methods
o NBE: the use of bacteria/cell lines require additional biochemical methods
to detect eg residual DNA, host cell proteins, immunoaffinity leachables
etc.
o These methods analyze on different levels of sensitivity, and hence:
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, o Purity and content determination is fundamentally different compared to
methods employed for NCE’s (!)
Biological (Biosynthetic, Biochemical) and biotechnological (rDNA) products
together, defined
a) Molecules originating from biosynthetic production
b) Originating from animal/plant or cellular material
c) Production on basis of rDNA technology
Their general term is complex active ingredients/ products which may be viewed
simply as:
(1) coming from living organisms and/or
(2) cannot be fully characterized by physical and/or chemical means
Gene therapy
- Exogenous genetic material is transferred into somatic cells to correct an
inherited or acquired defect
- It may also be used to introduce a new function or property into cells
- Gene therapy has been applied to diseases such as cystic fibrosis,
hemophilia, sickle cell anemia and diabetes
- Ethical consideration does not permit intervention with germ cells
- Self renewing stem cells are used for therapeutic transfer of genetic materials
into end state differentiated somatic cells
- Since stem cells can renew themselves, the inserted gene will remain in place
throughout subsequent generation of differentiated cells or tissue population
Example: a patient’s cells (T lymphocytes) are harvested and grown in the
laboratory.
Take gene into virus, put virus into a certain place. Virus produces not the protein
leading to survival and amplification, but the protein you want it to produce. In
this way the virus does not spread in the body but stays at the place. If you do
not use it correctly, protein artificially used in body will be passed to the next
generation (this scares people)
Nucleotide blockade/ antisense technology
- This technology focuses on the study of function of specific proteins and intra
cellular expression
- The sequence of a nucleotide chain that contains information for protein
synthesis is called the sense sequence;
o Nucleotide chain complementary to the sense sequence is called the
antisense sequence
- Antisense drugs recognize and bind to the nucleotide sense sequence of
specific messenger RNA (mRNA) molecule and prevent the synthesis of
unwanted proteins and actually destroying the sense molecules in the
process
- For producing antisense RNA in a cell by cloning techniques, the specific gene
of interest is cloned in an expression vector in the opposite orientation than
the mRNA to be neutralized
- A complementary mRNA is thus created to match mRNA produced in a
disease causing upregulated level
- When the two mRNA strands complex together and form a double helix,
translation to form the disease producing protein is prevented
Reduce expression of protein→ make antisense RNA (is opposite of mRNA). Will
form helix with sense RNA. Stop RNA that is producing the protein you don’t
want.
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