Avid Bioservices Inc (CDMO)

[Protector]

A case for binding the PS-Ligand vs PS-Receptor

The past days the difference between Bavutuximab binding to Phosphotidylserin, which we will call the PS Ligand, in stead of binding to the many PS-Receptors (as in Axl,TIM-1,TIM-4, TIM-3, Macrophages M2, MDSC's, etc as illustrated on this slide) has been emphasized.

In analogy also the anti-PD family of antibodies must make this choice. PD-1 binds to a PD receptor on the T-Cell while the anti-PD-L1 binds to the PD ligand expressed on the tumour cell surface. Yet when it comes to avoiding the PD-L1 ligand to bind with the PD-1 receptor on the T-Cell they BOTH reach there goal.

However two things need to be said, before we go into the case. Binding to the PD Ligand, just as with the PS Ligand, keeps ALL PD-1 receptors, no matter on what cells they find themselves from binding with the Ligand. Furthermore we do not know what binding to the PD-1 T-cell receptor may cause to the overall behaviour of that T-Cell once it is bound. From the T-Cell's perspective, once the anti-PD-1 is bound to it, this T-Cell which is UNAWARE of such thing as an artificial anti-PD-1 now thinks it is bound to a body cell (were it normally binds to the PD-1 Ligand). But in practice that is NOT THE CASE, the T-Cell still floats in the bloodstream with an anti-PD-1 attached to it.

Now based on the above and the article in this link (Body's immune system may play larger role in Alzheimer's disease than thought) we can see what the possible consequences are for doing that. I am not saying that the anti-PD-1 strategy could cause Alzheimer, I just want to illustrate how binding an anti-PD-1 to a T-Cell receptor, instead of the Ligand, may impact other processes.

In Alzheimer plaques of beta-amyloid are the cause of the disease. With people that do not develop Alzheimer the beta-amyloid is constantly removed in sufficient amounts so that things stay within acceptable boundaries. However, with Alzheimer - as the article also explains - the removal process cannot keep up and the beta-amyloid plaques grow behind a point where the signs of the disease start to surface and show.

The scientists in the article found that the T-cells and B-cells, part of the immune system BUT NOT present in the brain (because they CANNOT pass the brain blood barrier) play a role in producing antibodies which CAN pass the brain-blood barrier and accumulate in the brain where they associate with microglia to remove the beta-amyloid plaques.

So for the case I want to make, and I know the article says that mainly the B-cells produce these antibodies but I am illustrating a CONCEPT here that applies to lymphocytes in general (T,B,NK), we can ask ourselves the question what would happen to that process if the lymphocytes is bound to something that disables that function.

This brings us back to anti-PD-1 versus anti-PD-L1 and by extension anti-PS-R (receptor) and anti-PS-L (ligand).

When our T-Cell binds to the anti-PD-1 and believes it is now attached to a body cell it will very probably not play its many other roles any more. It thinks it has performed its function (well 'think' is a matter of speech :) and will do NOTHING any more. Yet in reality it is just still floating in the bloodstream. But since anti-PD-1 is a substance that is injected in the bloodstream it does NOT DISCRIMINATE between T-Cells when it meets one and can bind to its PS-1 receptor. So T-Cells will be brought in the disabled state all over the bloodstream and hence all would think they are now attached to a PD-L1 ligand of a cell.

From there one could easily start to understand the side effects. T-cells, which play a MAJOR role in the immune system, have been disabled.

Yet, the anti-PD-L1 (and in PS targeting the anti-PS-L) do NOT have that effect. The anti-PD-L1 binds to the PD-L1 ligand, achieves the same function as the PD-1 binding, but does NOT affect the T-Cell in ANY way.

In the same reasoning Bavituximab keeps M2 Macrophages and MDSC from binding with PS but in NO WAY affect the M2s or MDSCs normal workings. preventing the binding just prevents the M2/MDSCs to think an appoptic cycle is the reason for all the PS the see and hence suppress secretion of immune activating substances. When anti-PS-R drugs however bind with their respective receptors on all kinds of cells then they keep the original PS-Ligand also from binding BUT technically there is something attached to the cell now that must be perceived as PS. And why would that not result in the cell behaving as if PS (the original) itself was attached to it? If if that is so then we know what the result is (at least we do for M2 macrophages and MDSC's).

So why take all those needless risks and the possible side effects that come with it if one can bind to LIGANDS.

So the case I am making here is that with Bavituximab (binding to the PS ligand and not to PS receptors) and AstraZeneca's Durvalumab (which is an anti-PD-L1 and hence binds to the PD-L1 Ligand on the tumour cell and not to the PD-1 receptor on the T-Cell as does Opdivo which is an anti-PD-1) is a strategically strong long term combination that will very probably cause way less problems then all the T-cell manipulation.

I would say that there is DIRECT T-Cell manipulation by binding to the T-cell receptors and which I would qualify more dangerous and long term unpredictable versus INDIRECT T-Cell manipulation where binding the ligand obtains the same results in an on top of that more generic way without all the extra risk.

One could easily add to that that if Axl, TIM-1/3/4, M2 Macrophages, MDSC's (and possible others) all have PS receptors that then in practice exposed PS is supposed to bind to ALL of them at the same time, not just one and not the others as is the case with the anti-Axl/TIMs. In the end those receptors are there to allow immune system participants to recognize cells that are in an appotic process and will die from others. So it makes no sense to prevent this information to be detected by some of them and not by others.

The Ligand binding achieves this "all or nothing" in an elegant way and without the need to know if there possibly are a dozen of other cells that also have PS receptors but that we didn't find yet. I think this is why Bavituximab is so safe, it does not create an imbalance by only affecting one type of PS-receptor on say, TIM-3, and not on all others.

We can therefore say that Bavituximab ALSO achieves the work of anti-Axl, TIM-1,3 and 4 and with its own M2/MDSC functions is actually already a COMBO of 6 on its own and 100% safe.

It also means that the IP that PPHM holds is the only valuable one in the PS arena, because for all other approaches you need all the IP of EACH and EVERY anti-PS receptor drug to obtain the same protection. And who know how many other cells in the body are PS aware?