Schenk D., Opinion: Amyloid-beta immunotherapy for Alzheimer's disease: the end of the beginning.
Nat Rev Neurosci 2002 Oct;3(10):824-8
From the full article (caveat, it is my summary):
1. The animal research is reviewed, lots of very good models
2. Basic biochemistry: Amloid Precursor protein is cleavage by beta-secretase one fragment is the beta-stub then cleavage by gamma?-secretase one fragment is the AmyloidBeta peptide42 (42 aminoacids legnth) this are the ones that forms the plaque and toxicity is triggered against the brain.
3. The Proposed Rx Immunological Approaches:
a.Active immunization with the whole AB42 (from Elan, known as AN-1792) and the only human clinical trials so far)plus adjuvant QS-21
b.Active immunization with AB42 fragments (especially the first 16 amino terminal portion) plus a carrier protein conjugate (from Who?)
c.Passive immunization with monoclonal antibodies against AB42 or its fragments (from Who?)
4. Mechanisms:
a. T cell activation
b. Microglia activation
c. Antibodies
d. one or all could work by: attacking/eliminating the plaque, decrease AB42 in serum, and/or preventing the fibrillar AB42 aggregation formation before becoming plaques...
5. Clinical Experience (human) with AN-1792:
a. whole AB42 plus QS-21 adjuvant given to subjects from one to several times
b. Phase I 24 subjects- preliminary safety
c. Phase I 70 subjects- multidosing and safety
d. Phase IIa, the main trial so far, 375 subjects recruited, 4:1 ratio then 300 got AN-1792 and 75 got placebo. This trial is trying to establish some efficacy evidence.
c. 17 of 300 (5.6%) different degrees of severity of meningoencephalitis confirmed with MRI or Csf changes.
Interestingly the author calls this a "small percentage", and apparently no deaths. Subjects got reaction from 1 to 3 doses.
d. Antibody levels in the affected subjects DID NOT correlate with meningoencephalitis, some with no detectable levels.
f. Therefore (caveat, this is the theory): AN-1792 strategy (active whole AB42 immunization) activation of T-cell and/or Microglia activation is/are the responsible mechanism/s for the side effect...
g. Then...Fragment/conjugate active immunization strategy (that it is known to activates T-cell less) or Passive monoclonals (that obviates T-cells altogether) should give no meningoencephalitis.
f. some evidence that direct brain or csf approach with monoclonals (just at the blood level) could work as fine (according to the peripheral-brain ration decrease levels idea).
6. AN-1792 trial is not dosing subjects anymore, BUT very importantly continues to follow up all the subject without breaking the "blind coding" for assesment of efficacy and it is expected to have the clinical results "into 2003".
There are seemingly chances that the drug does shows that it works, and that the side effect is not a deterrent, or at the least this trial is the harbinger of a refined approach (fragment, monoclonal, even an improved AN-1792) that will provide a good treatment for this devastating disease. |
