notes of MIT course By Prof Christopher Love - Koch institute
By Prof Christopher Love - Koch institute at MIT
Focus on protein therapeutics manufacturing using recombinant DNA technology.
- Define what a biologic drug is
- Describe why biologic drugs are important in the treatment of disease
- Summarize how cells were first used in manufacturing
- Explain why many modern biologic drugs are manufactured using cell culture
What is a biologic drug?
- biological drug (= protein therapeutic)
- blood components
Multi billion dollar industry
First test with penicillin:
low yield to high yield penicillin (over 1000 fold increase)
=> penicillin is protective measure of mold => stressing the mold will lead to higher production of defence?
diphtheria first antiserum
He found that by heating and inactivating the bacterial toxin that caused diphtheria, and injecting it into guinea pigs,
the animals were immune to lethal doses of the toxin.
Bio-manufacturing to Deliver High-quality Biologics
- Describe how a small molecule drug and a protein therapeutic differ.
- Name the 20 amino acids used to build proteins.
- Identify the four types of protein structure.
- Identify and categorize post-translational modifications.
- Summarize how small changes in the structure of insulin lead to large changes in function.
- Describe what an antibody is and how it can be used to treat disease.
Conventional drugs vs recombinant biologics
size difference analogy marble and football
In red the recombinant biologics in top 10 list
Small molecules are easier to produce by chemical synthesis
mimic compound or block pathway for example ibuprofen, blocking inflammatory reactions.
Due to the small molecule it can bind at a lot of other sites, creating side effects and unintended reactions. This is the reason of large scale failure in first round testing
Biologics ar impossible to chemical synthesis, they are grown. less side-effects thanks to hyper specific shape
in order to work well => drug needs to attach to:
they need to be exact and precise to activate a function
How larger the molecule, the easier something can go wrong (such as oxidation or substitution)
possible problem: aggregation
=> clustering of molecules, can lead to allergic reactions
Better filtration techniques are a solution for this problem
Small molecules are often given in pill form, the acidity changes the pill to the active ingredient. If a biologics would be used the same way, they would be destroyed - intravenous, intramuscular, subcutaneous injection or inhalation
Enzymatic: example insulin
special targeting: inhibit normal biological function
Protein vaccines: hepatitis B, influenza
2.2 introduction to amino acids
3D form of proteins = what is does and how
Primary structure: sequence of amino acids
Secondary: A-helix and B-sheets
the alfa helix support itself by hydrogen bonding between the carboxyl and the amino group.
Tertiary structure: interactions among all atoms in 3D space (cysteine covalent bonding of S in insulin)
Tertiary structure, how everything influence the position between other molecules including ionic bonds (charges), hydrogene bonds, hydrophobic
insuline is stored as a hexamer but activa as a monomer
Insuline has a tendency to clog together when it is released from hexamer,
insuline is engineered to prevent this
2.4 Post Translational Modifications (PTM)
PTM can be a cause of concern: toxic variables