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a. SL12101: The chemistry of drugs > L29 - Biologicals > Flashcards

L29 - Biologicals Flashcards

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1
Q

What are biologicals?

A

Medicinal products which are produced/derived from a living system
- whole organism, iolated cells
- aka biopharmaceuticals

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2
Q

What are types of biologicals?

A
  • blood, blood fractionation products
  • vaccines
  • therapeutic proteins
  • nucleic acids & gene therapies
  • cell therapies
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3
Q

Proteins vs small molecules drug (proteins): (8)

A
  • BIG (~5,000 >150,000 Da)
  • Synthesis (biochemical rxns (mostly), within cells)
  • Usually, very water soluble
  • No oral absorption
  • Not membrane permeable
  • No active catabolites
  • Variable circulating half-life
  • Success in the clinic (higher – can be highly specific)
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4
Q

Protein vs small molecules drugs (small molecule drugs): (8)

A

• Small (<1000 Da)
• Synthesis (organic rxns, within vessels)
• May have limited water solubility
• Variable oral absorption
• Membrane permeable
• Potentially active catabolites
• Variable circulating half-life
• Success in the clinic (lower)

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5
Q

Therapeutic effect: activation of receptor signaling:

A
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6
Q

What are antibodies? Produced by? What are they like?

A

Proteins produced by B cells in blood in response to foreign substances
- B cells derived from single ancestral B cell
- highly specific to their target antigen

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7
Q

What is the therapeutic effect: inhibition of receptor signaling? Eg. VEGF signaling, anti-TNF-a therapies

A
  • ligand binds to antibody
  • ligand binds to protein
  • antibody binds to receptor

= prevent harmful physiological effect

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8
Q

What is the therapeutic effect: inhibition of receptor signaling? E.g. human epidermal growth factor receptor

A

Herceptin (trastuzumab) is a mAb binds to HER2
- prevents ligand from binding
= no cell growth, as not activated

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9
Q

What are other therapeutic effects?

A

E.g. Rituximab
- used to treat certain autoimmune disorders and blood cancers

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10
Q

What are the steps in the production of therapeutic proteins?

A

Relies largely on recombinant DNA methods
- get mRNA from gene of interest
- reverse transcriptase to get DNA RNA hybrid
- DNA pol for cDNA

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11
Q

What are the steps in the production of therapeutic mAbs: hybridomas?

A
  • immunisation of BALB/c mice with antigen to stimulate antibody prod
  • isolation of antibody producing B cells
  • fusion and generation of hybridomas
  • selection of specific hybridomas
  • expansion of selected hybridoma to produce mAbs
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12
Q

What are the different types of mAbs that can be produced?

A
  • mouse
  • chimeric (half human, half mouse)
  • humanised (with complementarity determining regions
  • human
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13
Q

How do you scale up therapeutic protein production of bacteria?

A

Bigger vat

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14
Q

How do you scale up therapeutic protein production of mammalian cells?

A
  • more difficult and expensive
  • cell lines are adherent - microcarriers can be used
  • cells that grow in suspension are easier
    E.g. chinese hamster ovary (CHO) cells
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15
Q

What are the characteristics/properties of protein folding & stabilisation?

A

• Hydrophobic interactions (80% internal)
• Electrostatic (repulsions, ion pairing)
• H-bonding (– Inter- and intramolecular)
• VDW forces
• Steric effects
• Hydration
• Disulphide bridges

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16
Q

What are the 2 different irreversible protein inactivations?

A
  • conformational change
  • chemical changes
17
Q

What is conformational change like?

A

Formation of incorrect structures
- aggregation

18
Q

What are chemical changes like?

A
  • break peptide backbone
  • modification of important residues
  • change protein shape
    E.g. hydrolysis, oxidation, deamidation, glycation, disulphide bond rearrangement
19
Q

How does aggregation of therapeutic proteins occur?

A
  • folded monomer (become partly unfolded, folded clusters)
  • partly unfolded monomers (become party unfolded clusters)
  • become nuclei
  • nuclei can combine = oligomonomers and soluble filaments
    = soluble agglomerated aggregates
20
Q

What operations may denature or aggregate proteins?

A
  • Freezing/thawing – proteins are usually
    refrigerated so care is needed
  • Agitation (interfaces)
  • Sonication
  • Contact with silicone oil
  • Low or high pH
  • Low or high salt
  • Specific salts
  • heat
21
Q

What is an examples of aggregation?

A

Cooking an egg
- water-soluble
- breaks -SH
- reforms as S-S
- insoluble

22
Q

What interfaces can cause aggregation?

A
  • air-water (vials, IV bags)
  • oilr-water (silicone-coated syringes)
  • hydrophobic surfaces (IV set & bag)
23
Q

What are possible consequences of aggregation/denaturation?

A

• Altered solubility
• Hypo-potency
• Hyper-potency
• Off target binding (Adverse events, faster clearance)
• Patient may generate neutralizing antibodies (ATAs) (Makes drug ineffective, may break tolerance)
• Cross react with endogenous protein
• Or no effect

24
Q

What is gene therapy? Eg?

A

Replacing a faulty gene to cure a disease
- cystic fibrosis
- muscular dystrophy
- sickle cell anaemia
- huntington’s disease

25
Q

History of gene therapy:

A

1989 - first approved gene therapy trial (ADA deficiency)
1999 - patient dies from severa inflammatory reaction
2003 - 4/10 get leukaemia
2003 - first gene therapy product (gendicine)
2006 - oncorine reaches market
2012 - glybera approaves - first western gene therapy product

26
Q

What is done in gene therapy: delivering genes?

A
  • therapeutic gene inserted into plasmid in bacterium + bacterial chromosome
  • virus infects cells & deliver its DNA, not replicate (therapeutic gene replaces viral genome)
27
Q

What is gendicine?

A
  • rAd-p53 injection
  • head and neck carcinoma treatment
  • safe and effective
28
Q

What is glybera?

A
  • developed by uniQure, approaved by EU Nov 2012
  • treatment of lipoprotein lipase deficiency (LPLD)
  • inc fat levels in blood
  • administeres as one tine series of small i.m. injections in leg
  • AAV vector serotypes, particular propensity for muscle cells
29
Q

What are current genetic therapy targets?

A
  • cancer (antigen, anti-angiogenesis, antibodies, TSG, suicide genes, immunotherapy)
  • monogenic disease (gene mutation, CF, sickle cell anaemia)
  • infectious diseases (target viral/bacterial genes or host receptor genes)
  • cardiovascular disease (anti-angiogenesis)

a. SL12101: The chemistry of drugs (27 decks)

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