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Summary Innovative Therapeutics
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Innovative Therapeutics Summary NOTE: PARTLY ENGLISH PARTLY DUTCH
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Innovative Therapeutics05-09-2022 - Genomics, oligonucleotides, and gene therapy
A biological medicinal product or biological is a medicinal product of which the active substance
is manufactured by or originates from a living organism. Different biologicals include blood
derivatives, blood components, vaccination, allergenic extracts, gene therapy, recombinant
proteins, antibodies, and xenotransplantation. Origin of biologicals include mammal cells,
plants, humans, yeast, bacteria, baculovirus (insect cells), and transgene.
Diphtheria serum – Emil von Behring
Diphtheria-causing bacterium > introduce into horse > toxin spread in the body > antitoxin in
the bloodstream > antitoxin medicine.
First therapeutic protein is insulin; isolated from pancreas of dog.
Classification of biologicals based on function and application
HIV cancer vaccine (2 strains, prevent replication)
Benefits of biologicals
- Specific functions and activities
- Less risk of side effects
- Better tollerated: less immunogenicity
- Fast development and approval
- Intellectual property protection (patent molecules)
Nowadays around 50% of the top 100 medicines used are biologicals and conventional
medicine.
Molecular biotechnologies and genomics
A gene is the basic physical and functional unit of heredity. Genes, which are made up of DNA,
act as instructions to make proteins. In humans, genes vary in size from a few hundred DNA
bases to more than 2 million bases. The Human Genome Project has estimated that humans
have between 20,000 and 25,000 genes.
In prokaryotic cells, pro-polypeptides are formed which need protein processing to activity the
protein. This is important because it is not possible in other cells. Also, transport to cellular
destination is needed. Thanks s to this high degree of sequence conservation, porcine/bovine
insulin can be used to treat human patients.
Target selection (gene) > isolation mRNA from cells that express the gene of interest > reverse
transcription reaction > mixture of cDNAs > amplify selected cDNA using PCR > cloning into
suitable expression vector (foreign DNA to be inserted via ligation/electric shock > recombinant
DNA molecule) > transformation of E. coli and selection for ampicillin resistance > quality check
(sequence, orientation) > transfection of mammalian cells > stable expression is obtained by
selection for G418 resistance > selection of cells with the highest expression level > upscaling
,of cell culture > purification of the recombinant protein (downstream processing e.g.
chromatography) > quality check* > formulation > therapeutic protein suitable for human use.
*Process validation (removal of host DNA and proteins, viral clearance), consistency of the
manufacturing process, consistence of the drug substance (glycosylation, folding)
Expression hosts
Glycosylation (which may differ from humans)
Genomics stratey for new drugs discovery
In 2000 that scientists had finished the first draft of the human
genome. New reference genome came out in 2013. Fixed more
than 200 million base pairs in the reference genome. What’s
new: the human genome measures 3.05 billion base pairs. The
human genome contains 19,969 protein-coding genes. In 2021
more than 100 new genes.
System biology >>
,RNA/DNA micro array to compare patient vs antipatient
High-dimensional single-cell technologies for the analysis of cancer immunotherapy.
The gut microbiota is quite important for drugs and their design, and the gut is therefore also
called the ‘second genome’ or the ‘forgotten organ’. The human body has 10 trillion cells and
23.000 genes, but the gut microbiota has 100 trillion cells and 3.3M genes.
OMICs in precision medicine stratify patients and predict drug response to come up with
personalized drug therapy based on genotype (by use of bioinformatics).
, 06-09-2022 - Structuur en stabiliteit van eiwitgeneesmiddelen
Conventionele geneesmiddelen MW tot ca. 900 Da, eiwitgeneesmiddelen MW ca. 1 tot >150
kDa. Productie in biologische systemen (levende cellen). Generieke preparaten behoren tot
de conventionele geneesmiddelen.
De meeste targets voor geneesmiddelen zijn eiwitten. Hierbij horen het onderdrukken van het
ziekteproces door interactie met een eiwit of het vervangen van een eiwit dat bijdraagt aan het
ziekteproces.
Biologicals betreffen peptiden/eiwitten, vaccins, en ATMP’s (advanced therapy medicinal
products). Ongeveer 25% van de nieuwe geneesmiddelen zijn eiwitten, vooral ‘engineered
proteins’, orignators (patentbescherming), en biosimilars.
Eiwitgeneesmiddelen zijn opgebouwd uit aminozuren, nucleïnezuren, suikers of (complexe)
combinaties hiervan. Ze zijn vooral verkregen uit micro-organismen, dierlijke, of humane
bronnen. De productie is biotechnologisch, betreffende recombinant-DNA-technologie. Het
volledig beheersen van het productieproces en de continue kwaliteitscontrole zijn essentieel.
Primaire structuur: covalent gebonden aminozuren (amidebinding), vormen de ruggengraat
van het eiwit.
Secondaire structuur: amide (NH) is waterstofdonor, carbonyl (C=O) is waterstofaccetor,
vorming waterstofbruggen. Peptiden zijn 2 - ca. 50 aminozuren (geen tertiaire structuur).
Tertiaire structuur: grotere eiwitten zijn vaak gevouwen in verschillende structuurdomeinen.
Essentieel voor de functie en werking van het eiwit.
Quaternaire structuur: assemblage van stoichiometrische vast aantal tertiaire moleculen
(complex). Bestaat uit niet-covalente interacties, worden gestabiliseerd door zwavelbruggen.
Hydratatie: binding van water aan het molecuul. Water kan zich binden aan de buitenkant,
waar het vrij ‘los’ bindt. Water bindt ook aan de binnenkant (‘trapped’) waar het sterker
gebonden is (lagere diëlektrische constante). Watermoleculen spelen een belangrijke rol bij
de stabiliteit en functie van de eiwitten. Enzymen hebben een klein beetje water nodig voor de
werking, net voldoende om polaire groepen eiwit te bedekken (0,2g per g eiwit). Eiwit in
oplossing worden gestabiliseerd door o.a. suikers en aminozuren door interactie met
eiwitoppervlak.
Post-translationele modificaties:
In ER en Golgi vinden post-translationele modificaties plaats. Enzymatische koppeling van
suikergroepen (glycosylering), fosfaatgroepen (fosforylering) en sulfaatgroepen (sulfatering)
aan de primaire aminozuurvolgorde. Ook worden er disulfidebruggen gevormd, die belangrijk
zijn voor goede vouwing/functie/stabiliteit (open bij reductie > foute structuur > aggregatie).
Voor eiwitgeneesmiddelen zijn voor glycosylering en zwavelbruggen belangrijk.
Glycosylering:
Correcte glycosylering is erg belangrijk voor vouwing, stabiliteit en biologische eigenschappen.
Asparaginase residu = N-linked
Serine of threonine residue = O-linked
Er zijn grote verschillen in (vermogen tot) glycosylering tussen productiesystemen.
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