Avid Bioservices Inc (CDMO)

[freethemice]

CJ, thanks for putting all that together. One difference between the Ramesh et al JCI paper and what was reported on
in the AHA abstract is that in the JCI paper 2aG4 (mouse bavi) was used, and in the AHA abstract PGN635 (fully human bavi)
was used. In the AHA abstract they report on testing their three hypotheses developed from the JCI paper.
See the figure shown again below.
1) Block the chain of events in the pathway at the first step (ii in the figure below) from occurring by using PGN635,
this prevents the interaction between domain V of beta2-GPI and the end domain of apoER2.
2) Add more NO (nitric oxide) since the pathway results in a reduction of NO production. They did this by adding the NO
donor S-nitroso-N-acetylpenicillamine.
3) Block the production of apoER2 which would also block the first step. They did this by using a short interfering RNA
(siRNA) to destroy the messenger RNA that codes for the gene for apoER2.

I believe the endothelial migration which is restored by these three methods is part of the normal endothelial
repair mechanisms. VEGF (vascular endothelial growth factor) is part of this process.
So what does all this mean? My guess is that PGN635 could be given to patients with APS to reduce thrombosis.
It would work by competing with the pathogenic autoantibodies for binding to beta2-GPI. Enough bavi would
saturate the binding to beta2-GPI using domain II and thus block any attempts by the autoantibodies to bind via domain I.
The other two mechanisms, adding NO, and blocking apoER2 production, might have more systemic side effects.