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Pi3k pathway is similar to PS in that both have cross reactivity function to normal endogenous human cell physiology.
The two ton elephant in regards to targeting pi3k is finding a therapeutic balance of proliferation versus differentiation. That is why you are seeing several (split) targeting therapies. The race is on to finding that cross reactivity endogenous balance of proliferation versus differentiation..
With that said, antiPs has (2) two ton elephants, binding and cross reactivity..
Electroporation is a derivative of all of the above. All of which are related to electric current to cellular membrane.
Understanding that the tumor mass is made of tumor cells, and that the outer part of a tumor mass is neoplasmic cells and stromal cells, all of which consist of cell membrane.
The function is to electropulse a cell membrane in order to create cellular permeabilization, and thus creating a pore for DNA/drug/antibody translation.
There is plenty of incorrect scientific reasoning on Ihub.
But I prefer to delineate what's plausibe and physiologically possible, in terms of science and investing in such. Otherwise, there's a lot of dart throwing..
I'm not saying that it's impossible, as there are studies dating back to the 1980's that prove such. However, as citation has shown, the cell kill rate and reasoning behind such techniques didn't equate to advancement. For example, what would be the point of injecting (Keytruda) anti PD1/L-CTLA4 inside a cell?? The therapeutic action (target) takes place outside the cell... The same could be said for AntiPS..
The transition from Cellular pathogenesis to normal apoptotic cell cycle starts by immune recognition of "self", from "non-self" in a tumor mircoenvironment.. The issue with oncogenesis is that once this is broken down, it's difficult to revert the transformation.. It's possible to remove (surgical) and kill (chemo) tumor cells, but transitioning them is difficult.. But, not impossible..
The ability to transition is multifaceted, and as I mentioned would require recognition of non-self, or in the least recognize the deception by which tumor cells avoid apoptosis. It's unlikely that one single therapeutic would be able to change the "decoy" and at the same time circumvent the "transition" abilities of oncogenic cellular chemistry to survive. In other-words recognize, and alter tumor DNA's limitless life cycle.
However, if the goal is to change tumor DNA for the purpose of altering it's offspring, then the only way would be intracellular (intratumorally), as opposed to extrocellular manipulation.
So, this is what EP DNA Presenting technology is trying to execute, IMO.. Present Plasmid DNA that alters mitotic tumor cell code, into cells that obey the "Hayflick Limit".. Then and only then would there be systemic abscopal effect, IMO..
Okay, but based on what I've read there seems to be a disconnect between science and real understanding.. And for those that understand science it comes across as "not having it"..
EP in the science community is not confusing.. It's not yet commonplace as a vector vehicle, but progress is being made, in regards to its potential. This is true as more confirmatory trials are conducted..
I'm not sure if you're old enough to remember the original Star Trek series, but the Starship Enterprise had a physician whose name was "Bones", and In several episodes you would see him using a device that resembled an EP device. He would treat his patients, and cure whatever illness they had using this device, all the while doing so without breaking the exodermis..
The point being, that this is the future of medicine, and as time passes it will be proved out, and commonplace..
If you would like I can try and help explain exactly what manifest EP is eliciting, and what the immunomodulatory effect is on any physiologic level.. Just ask specific questions..
Hindsight is 20/20, but, addressing the 2 ton elephant should have been priority one. Especially considering what has been known since the beginning (see Dr Thorpe's patents, and the latest patent, betareceptors, betabodies.)
Money (investors expense I might add) would have been well spent to move this forward..
I would have started there.
And what about the Chemo Combos that we've been force fed? This is fundamentally flawed, IMO. Inhibiting the immune system in order to gain more PS? Think about that.. more immunosuppressive PS in hopes to dock more Bavituximab? It should have been less is more, not more is better.. And we've, they've known what the data mining has told us years ago, and that is BINDING IS WEAK.
I would have done everything possible to move antips forward with Radiation..more direct targeting, with less immnomodulatory consequence, IMO.
I would have been more investor friendly too :)
I will post more about what they should do now, when time allows.. But of course it would include Statins, and there's other synergistic molecules that need to be looked at as well..
PS functions as a nucleation to reestablishing ER during telophase of cytokinesis. This would suggest that PS remains negatively charged, imo.
However,
I've suggested it would lose electrostatic magnetism during an apoptotic event. As a loss off cellular asymmetry would theoretically effect the molecular cation, ion environment.
B2GP1 Levels were taken pre-treatment, I'm assuming this would have included Chemo. The data mining is saying that B2GP1 levels pre-treatment had a stat sig PD biomarker.
Also, chemo destroys cells specifically during the mitotic stage, thus the diluting bonding effect doesn't seem plausible. This needs further clarity to be known for sure though..
R&D should have been the focus in this regards. Instead investor resources were wasted on what was already, or should have been known, because if I knew since 10 years ago and suggested 4, how could they have not known?
Why are they wasting more time and money (2 mill for NCCN, MSK, AZN Etc..) when they know the product is flawed, and a better product is patented??
Are they just going to use Bavi as a failed guide to find biomarkers? What's the point, if a better binding antiPS is needed.
The p3 trial proved the two ton elephant in the room. Thus the 30% data mining..
Anti Ps is not the issue. However as the data mining suggest, and what ive suggested the past 4 years, binding is.
Also, the fact that phosphatidylserine has endogenous cross reactive manifest properties, makes it targeted double jeopardy, so to speak..
Not to mention the issue of molelectrostatic bonding that B2GP1 initiates.. As you can see, and what is scientifically known about B2Gp1, its a crowded, cross reactive protein.. Lots of competition for a clumsy therapeutic, imo..
Just FYI, cytokines regulate inflammatory immune response within pathogenic manifest.. The lack of an inflammatory immune response in regards to Bavituximab is multilevel in regards to different immune cytokine milieu.. It would be long winded, and inappropriate of me to go indepth on this board.
I would like to discuss EPIL12's MOA as time allows..
History has shown (mouse studies, preclinical, clinical) very little adverse immune reaction to Bavituximab, such has been seen with most Monotherapeutic MaBs (Provenge, Yervoy, Keytruda, etc)
The defense has been, Bavituximab eliciting an upstream response, and reduction in IL10 and an increase in IL12 within the tumor mircoenvironment, thus allowing immature dendritic cells to mature into tumor specific APC's..
This theory has holes, and I've had the argument many times over there.
I'm super interested in EP-IL12. It seems logical and scientifically plausible. Not to mention, some what easy to understand.
Isn't it possible that some of the cohorts in the Sunrise trial, where already taking Statins, especially since the vast majority of NSCLC patients are/were smokers? Is it possible that approximetley 30% of this trial were on statins, or had been previously?
And didn't the data mining numbers show 30% of cohorts had optimal e2gp1 levels? Wow I wonder if there is any correlation??
That's 1 of 3 (two ton elephants) in the room, and forget b2gp1 as a reliable marker for Bavituximab, as we know it, imo.
1)Binding 2)Endogenous Cross Reactivity 3)Management (The loss of Dr. Thorpe (RIP) has come to roost). If ever we needed him, it is now.
Just a note on cross reactivity. It's my opinion that Bavituximab is the least-common denominator in competition for b2gp1, insomuch that it's not interfering with normal endogenous functions, thus the lack of systemic immune AE's, IMO..
1. Age (This is the #1 factor for "free floating, unbound B2GP1). 2. Smoker/Non 3. Race 4. Arteriosclerotic Vascular Disease 5. Weight 6. History of APS 7. History of coagulants 8. Overall metabolic health 9. Diabetes 10. Inflammatory disease
Ab2gp1 is only expressed when bound/exposed/expressed to lipid by-layer domain V 1,2.
B2gp1 is "free floating" and readable in plasma. Which by the way exist in two separate conformations.
I'm assuming "free floating" samples were taken pre-administration in Sunrise trial. The data mining was not for relevant antibodies directed towards b2gp1, IMO.
See confirmation from your study link below>>
I've searched the best possible abstract to enlighten anyone interested in knowing what and how B2GP1 functions.
BTW, there is confirmation in the abstract to my statin/bavi theory..