Smart Drugs/Antibodies

What are the requirements for a molecule to be able to cross the BBB

Without a specific protein transport system, in order to cross the blood-brain barrier, a molecule must:

1. Have a molecular weight of less than 300

2. Have a clogP of no more than 3

3. Have no more than 3 hydrogen bond donors

4. Have no more than 6 hydrogen bond acceptors

How does L-DOPA cross the BBB

It exploits the alpha-amino acid shuttle protein, where anything with the L-amino acid group is transported.

What is an example of a bipartate drug

CarbiDOPA. It competitively inhibits DOPA decarboxylase and forms a complex (acetaldehyde linkage) with it in the blood.

Sentry drug - protects the active drug we want to deliver from being degraded

What are IgM antibodies

The first response to an infection → large pentamers that are less specific

Are good at promoting agglutination

What are some features IgG antibodies

Secreted after IgMs, made up of 4 peptide chains linked together via cys-cys disulfide bonds, with two antigen-binding sites.

Bind directly to pathogens, inactivating them or marking them for destruction.

Present for a long time after infection.

Mr - 150,000

What are ADCs

Antibody drug conjugates

• 3-5 drug molecules are covalently attached to the antibody (lysine residue - COOH, aspartate/glutamate residues - amine groups)

• Antibody can attach to the outside of the cell (CSM protein or oligosaccharide) and deliver the drug (must be very potent)

• Covalent bonds are designed to break under certain conditions

How do ADCs release the active drug into cells?

If the ADC binds to the right receptor on the cell membrane, it will stimulate endocytosis.

The ADC is engulfed and contained within an endosome

As the endosome moves from the early to the late stage it can either be recycled or form a lysosome

The pH of the lysosome gradually drops, and the protein is degraded, hopefully releasing the active drug into the cytoplasm

How can ADCs target tumour cells

Tumour cells may have an overexpressed cell membrane protein or oligosaccharide so the ADC is able to selectively bind

Why would you use an antibody enzyme conjugate over an ADC

You can only attach 3-5 drug molecules to an antibody so the dosage is low. If you deliver a specific enzyme to target cells that enzyme can be used to convert prodrug molecules to active drug molecules.

What is ADEPT

1. Antibody Directed Enzyme Prodrug Therapy

2. Tumour cells overexpress target antigen

3. Inject Antibody-enzyme conjugate and wait for it to immobilise on target cells

4. Add prodrug molecule

5. On target cells the enzyme will catalyse the formation of the active drug

6. Active drug is taken up by target cells
   

What is HAMA

Human Anti-Mouse Antibody

Previously, antibodies for ADEPT systems were made using adapted mouse antibodies, so could only be used as a one time treatment. The human body recognised the foreign antibodies and starts producing antibodies against them.

Now less of a problem as we can engineer mouse antibodies so that the body does not recognise them as foreign.