Replies to post #73319 on Avid Bioservices Inc (CDMO)

[Protector]

FreeNorth, it is not like that.

Since the exposure of phosphatidylserine on a cell's surface flags it as apoptotic to the immune system and needing removal, what additional benefit does Bavituximab add to the removal of the cell?

PS is a body own substance that when exposed on the outside of a cell keeps the immune system from cleaning up that damaged/infected cell. PS, under normal circumstances, is only present in the Body at the inside of the cell membrane. Bavi binds with one arm to the PS and on the other side advertises something the immune system will want to clean-up. In this way it keeps PS from protecting the cell from clean-up.

If PS is exposed on blood vessels to tumors (vessels that should not be there in the first place and have little cell cracks) it also results in these vessels left alone unless Bavi binds also to that PS to attract the immune system.

Finally, viruses that enter a cell to get replicated in the kernel (where the DNA is and where RNA replication can take place) cannot get there without passing the cell's membrane and be marked with PS as a result. So Bavi will also bind to the PS on those viruses and the immune system will clean them up as-well.

How well Bavi works for a given viral condition depends on the type of cell and viral interaction. Some cells kind of explode (burst) because so many viruses are reproduced that the cell can't hold them, some, as described on the Peregrine pages, see a virus come in and leave to go to the next cell (well go! a virus is not a living thing, it's a string of DNA with or without envelope). All now depends how many where in contact with PS. Bavi may work better in the second scenario then in the first (bursting cells) because in the first many viruses may come in circulation without PS and therefore keep ahead in infecting other cells. This would look like a kind of latency (which probably was observed in the Military Contract). In the case of Ebola for instance this latency is not acceptable for us because Ebola acts very fast (1 week incubation and about max 72 hours before death - internal bleeding).

Subject for the real scientists to correct.

[entdoc]

FreeNorth,excellent question, post#73319)in which you asked, "Since the exposure of phosphatidylserine (-PS) on a cell's surface flags it as apoptotic to the immune system and needing removal, what additional benefit does Bavituximab add to the removal of the cell?"
I think the key concept is the use of the term "flags it". Actually, the opposite. Apoptosis and inverted -PS is a normal process that is all but ignored by the body, and those dying cells are left for the usual "weekly garbage collectors" rather than specialized detox cells. It is thought that the production of cancer cells also allows these early cell clones to fly below the radar of the specialized 'self-non-self' hazmat crew that brings in cytokines, and full-blown allergic/inflammatory response to invasion.
Anti-PS agents such as Bavituximab grab onto all flipped -PS, whether from normal apoptotic cells or cancerous cells, and especially on the specialized endothelial cells of blood vessels nourishing cancers.
What we found on the way to the bank (!!apropos of today's discussions!!) is that somehow Bavi excites the rapid inggress of the hazmat crowd of dendritic cells, etc. to the region, and thus acts as a non-specific immunological stimulus at tumor sites. This is, perforce, a relatively weak, but apparently measureable effect, and that is what is being measured now in clinical trials. We know that similar non-specific immunological enhancers have relatively weak effect, but if it is measureable, repeatable, and free of side-effects...why not use it? We have only begun to scratch the surface of this vast new technology, and are privileged to be on the forefront of a true phenomenon with vast potential for good. The key is that time and again the platform (anti-PS MAB) is being shown to be relatively safe. Imagine what the warhead can be armed with. This website might help for basic definitions: http://www.caring4cancer.com/go/cancer/treatment/other
I posted the following 6 month-old (non-Thorpian) article a couple days ago, and it is absolutely fascinating in its implications for stem cells and for genetically engineered molecules:
"This study was performed...to identify potential targets for the development of novel therapy to treat cancer with poor outcome or treatment efficacy. We show that the negatively charged phospholipid phosphatidylserine (PS) is exposed in the outer leaflet of the plasma membrane not only in tumor cell lines, but also in metastases and primary cultures thereof, which contrasts with a lack of PS exposure by differentiated non-tumorigenic counterparts. Studied tumor cell lines were derived from non-tumorigenic and malignant melanomas, prostate- and renal cancer, glioblastoma and a rhabdomyosarcoma. Importantly, also metastases of melanoma expose PS and [!]there is a correlation between malignancy of melanoma cell lines from different stages of tumor progression and PS exposure[!]. The PS exposure we found was neither of apoptotic nor of experimental artificial origin. Finally potentially [!]malignant and non-malignant cells could be differentiated by sorting of a primary cell culture derived from a glioblastoma based on PS exposure[!], which has so far not been possible within one culture due to lack of a specific marker. Our data provide clear evidence that PS could serve as uniform marker of tumor cells and metastases as well as a target for novel therapeutic approaches based on e.g. PS-specific host defense derived peptides. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175029/
http://cancerres.aacrjournals.org/content/early/2011/03/16/0008-5472.CAN-10-3894.abstract