Wednesday, November 07, 2012 4:42:47 AM
antibodies (aPL), and on the target of these antibodies, beta2-glycoprotein I (beta2-GPI), is vast.
The following is from the introduction in last year's paper by Ramesh et al.
Here is figure 8 from the paper which summarizes some of the above, and what was found in this study.
This shows two molecules of beta2-GPI bound to PS on the surface of endothelial cells lining a blood vessel.
In APS this is not usually a tumor blood vessel, but the same will apply there too.
The two molecules of beta2-GPI are bound by the antiphospholipid antibody so that they are "dimerized",
which just means the two of them connected to each other. Note that the antibody is bound to
domain I of both of the beta2-GPI molecules. It has been found that these natural antibodies which bind
to domain I are highly associated with the thrombosis effects of APS. So what seems to happen is that
the domain V of the beta2-GPI molecule will interact with the end of the apoER2 receptor which is nearby.
This could be some sort of electrostatic effect because domain V has a positive charge. When this happens
a signal is propagated through the plasma membrane and the cytoplasmic tail of the apoER2 then interacts
with the enzyme PP2A. This causes PP2A to remove a phosphate group from the enzyme eNOS,
which is attached to the inside (cytoplasmic) side of the plasma membrane. The S1179 refers to the
amino acid Serine at position 1179 of the enzyme. PP2A is a phosphatase, which is an enzyme that
adds and removes phosphate groups from other molecules. The removal of this phosphate group
reduces the activity of eNOS, which means it produces less NO (nitric oxide). This then causes more
white blood cells to stick to the walls of the blood vessel which causes increased thrombosis.
It is complicated, but this chain of events is how a signal from outside the cell can get transmitted across
the cell membrane to the inside (cytoplasm) of the cell to turn on/off the production of molecules like NO.
In other cases signals can be carried into the nucleus so that genes can be turned on or off.
This process is called a signal transduction pathway.
The researchers found that by using a version of bavituximab, which binds to domain II of
beta2-GPI this pathway was broken because apoER2 would no longer bind to
domain V of the beta2-GPI bound to the plasma membrane. Without this happening a signal was
not sent down the pathway which means the PP2A did not remove a phosphate group from eNOS and
the production of NO was not reduced, so thrombosis was not increased. Therefore, bavi blocked the
chain of events and prevented the thrombotic effects of APS. This probably works because by
binding domain II, instead of domain I, there is a small change in the shape of the beta2-GPI,
maybe a twist in the structure, that results in the failure of the interaction between the domain V and
the end of the apoER2. That is the way it is many times, very small changes are all that is needed
because we are working on the atomic scale and the three-dimensional structure is very important.
The abstract from the AHA presentation also says that the aPL inhibited the normal repair of blood vessels
and that PGN635 allowed the repair to happen.
My thoughts on this are that PGN635 (fully human bavi) could be used when APS patients are having
acute episodes to prevent thrombosis. Of course, this would have to go through the whole clinical trial process,
but the large amount of safety data on bavi will help. I would guess that the reduction in thrombotic events could
be the trial endpoint, and that could mean a reduction in deaths too.
Here is a diagram showing bavi binding to domain II.
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