BBB L4 Flashcards
What are the Advantages of using Ab or biologic therapeutics?
- High specificity –> target single aspect of disease e.g.
- Reduce amyloid peptide production
- Reduce tau neurofibrillary tangles
- Apoptosis
- Deliver growth factors
- few s/e elsewhere in the body
What are the Disadvantages of using Ab or biologic therapeutics?
Very large, 150 kDa - hard to cross BBB
Why is there a lack of success for these molecules and what evidence shows this poor success
- results poor for crossing BBB
- no previous/current trials targeting BBB
How can we optimise Ab delivery for the BBB? (2 approaches)
1) Ab and RMT approach - use ‘trojan Ab’
2) Bi-Specific i.e. Trojan and Therapy in one Ab
How is the Ab that targets RMT made?
Using human TfR –> put into rabbit –> rabbit expresses Ab against TfR –> harvest Ab for TfR –> use as trojan
Give an example of a formulation made for Ab-RMT and the disease it targets
HIR (Human Insulin Receptor) with GDNF (Glial cell Derived Neurotrophic Factor)
Targeting Parkinson’s Disease
Ab attaches to the HIR at the BBB - enables transcytosis and delivery of cytotoxic payload
This showed off-target effects due to accumulation in the liver and spleen - little in the lungs = beneficial.
What were the effects of HIR + GDNF Ab?
Explain why.
- Pacreatic toxicity
- Fibrosis and lesions
Even with low doses = due to abundance of insulin receptors in the pancreas
What is a Bispecific Ab?
Given an example and what does this treat?
One = trojan, One side = therapeutic
- Trojan = TfR
- Therapy = BACE1 enzyme (for breakdown of amyloid protein)
- Treats Alzheimers disease
How are the bispecific Ab made?
Combine two Ab - Heavy and Light chains from each of Ab’s with Trojan and Therapy
What problems are encountered with use of Trojan Antibody therapy?
- too high affinity
therefore they get stuck in vesicles upon endocytosis, as well as stuck in the blood-side of the BBB = not reach cell.
How is the problem of too high affinity resolved for Trojan Ab therapy?
Reduce the affinity BUT still need efficacy, therefore, balance:
- Lower affinity
- High brain uptake
i.e. low affinity but not too much so doesn’t bind TfR, but need enough affinity to still allow therapeutic action
What were the effects seen in the optimised TfR/BACE1 Bi-specific Ab?
- Increased BACE1 levels in brain = decreased amyloid protein (by approx. half)
- reduced amyloid = shows restoration of cognitive ability - due to threshold of amyloid = regain cognition
What are the limitations with use of Ab therapy?
- Very expensive
- Need high synthesis rate
- Only administered IV = compliance issue (need to be in hospital)
- Cannot administer large depot = due to protein overload = need to give over hours
