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Replies to post #267192 on Avid Bioservices Inc (CDMO)
PPHM's Bavituximab and new BetaBodies however CAPS PS itself thereby disabling it from binding with all 12 PS receptors at ones and hence avoid not only suppression by the immune system but also stimulates the immune system to activate (which is a requirement).
If Phosphatidylserine gets exposed it will WITHOUT DISCRIMINATION affect and bind ALL above PS receptors at the SAME TIME thereby implementing a global/upstream/systemic strategy to suppress the Immune System from intervening in the Natural Cell Death cycle (apoptosis).
One can immediately see that binding only TIM-1 as does Celldex or TIM-3 as does Novartis, or Axl as does Genentech doesn't implement a GLOBAL approach but just disables ONE specific receptor from binding with PS.
PPHM's Bavituximab and new BetaBodies however CAPS PS itself thereby disabling it from binding with all 12 PS receptors at ones and hence avoid not only suppression by the immune system but also stimulates the immune system to activate (which is a requirement).
Therefor acquiring the patents of PPHM, that cover this broad global approach achieve several things:
- no 12 different drugs needed in I-O combination
- no 12 dosings needed (because all these types of receptors do NOT occur in the same amounts)
- no mine-field of clinical trials to test all these combo's with PD-1, PD-L1, CTLA-4, etc.
- next generation not needing the presence of blood already available
- much higher binding instance because Bavituximab binds the exposed PS on non-mobile cells and reduced amounts in micro vesicles while all others target receptors on immune system cells that move and would have to meet THEIR PS receptor compatible molecule (out of 12) to bind.
- NO T-Cell PS receptor ONLY binding involved (wanted or as side effect (see TIM-3).
- immune system suppression BLOCKING and immune system stimulation at the SAME time
- Immune Response against relapse possible because of that and ONLY because of that.
Additionally other measures are possible. One can try to give transfusions to REMOVE floating PS from the blood stream WITHOUT ANY HARM DONE and so doing lower the amount of PS! One can not do that to the Immune-Cell holding the above mentioned PS Receptors because those cells are NEEDED.
So personally, while I agree that CEO King said that PPHM does not own the complete PS field, I think PPHM holds the patents to the ONLY strategy that can GUARANTEE that a PS molecule, when CAPPED, is disabled for ALL PS receptors at the same time and that wit ONE SINGLE drug to add to a combo.
Furthermore this works for Oncology, Inflamations/Infections, Viral, Surgery/Injury and actually in ALL CASES where a cell exposes PS while NOT due to the natural cell death cycle and where it mistakenly has the side-effect of suppressing the immune system.
PPHM holds all those patents.
several PS receptors were added. We now have the PS receptors on
IMC: MDSC, Macrophages, T-Cell
TIM: Tim1, Tim3, Tim4
TAM: Axl, Mer, Tyro-3
Others: CD300a, RAGE, BAI-1, Stabilin
If Phosphatidylserine gets exposed it will WITHOUT DISCRIMINATION affect and bind ALL above PS receptors at the SAME TIME thereby implementing a global/upstream/systemic strategy to suppress the Immune System from intervening in the Natural Cell Death cycle (apoptosis).
The new research also suggests that Zika virus learned to exploit something of a secret passage, a cell surface molecule known as AXL, while West Nile and dengue viruses did not.
"Zika uses AXL to efficiently slip past one of the major barrier cell types in the placenta: fetal endothelial cells, which are the gateway to access fetal circulation," said Choe.
...
https://www.google.com/amp/s/medicalxpress.com/news/2017-02-scientists-clue-zika-relatives-birth.amp
If Phosphatidylserine gets exposed it will WITHOUT DISCRIMINATION affect and bind ALL above PS receptors at the SAME TIME thereby implementing a global/upstream/systemic strategy to suppress the Immune System from intervening in the Natural Cell Death cycle (apoptosis).
One can immediately see that binding only TIM-1 as does Celldex or TIM-3 as does Novartis, or Axl as does Genentech doesn't implement a GLOBAL approach but just disables ONE specific receptor from binding with PS.
PPHM's Bavituximab and new BetaBodies however CAPS PS itself thereby disabling it from binding with all 12 PS receptors at ones and hence avoid not only suppression by the immune system but also stimulates the immune system to activate (which is a requirement).
Therefor acquiring the patents of PPHM, that cover this broad global approach achieve several things:
- no 12 different drugs needed in I-O combination
- no 12 dosings needed (because all these types of receptors do NOT occur in the same amounts)
- no mine-field of clinical trials to test all these combo's with PD-1, PD-L1, CTLA-4, etc.
- next generation not needing the presence of blood already available
- much higher binding instance because Bavituximab binds the exposed PS on non-mobile cells and reduced amounts in micro vesicles while all others target receptors on immune system cells that move and would have to meet THEIR PS receptor compatible molecule (out of 12) to bind.
- NO T-Cell PS receptor ONLY binding involved (wanted or as side effect (see TIM-3).
- immune system suppression BLOCKING and immune system stimulation at the SAME time
- Immune Response against relapse possible because of that and ONLY because of that.
Additionally other measures are possible. One can try to give transfusions to REMOVE floating PS from the blood stream WITHOUT ANY HARM DONE and so doing lower the amount of PS! One can not do that to the Immune-Cell holding the above mentioned PS Receptors because those cells are NEEDED.
So personally, while I agree that CEO King said that PPHM does not own the complete PS field, I think PPHM holds the patents to the ONLY strategy that can GUARANTEE that a PS molecule, when CAPPED, is disabled for ALL PS receptors at the same time and that wit ONE SINGLE drug to add to a combo.
Furthermore this works for Oncology, Inflamations/Infections, Viral, Surgery/Injury and actually in ALL CASES where a cell exposes PS while NOT due to the natural cell death cycle and where it mistakenly has the side-effect of suppressing the immune system.
PPHM holds all those patents.
Phosphatidylserine Reversibly Binds Cu2+ with Extremely High Affinity
Abstract
Phosphatidylserine (PS) embedded within supported lipid bilayers (SLBs) was found to bind Cu2+ from solution with extraordinarily high affinity. In fact, the equilibrium dissociation constant was in the femtomolar range. The resulting complex formed in a 1:2 Cu2+ to PS ratio and quenches a broad spectrum of lipid-bound fluorophores in a reversible and pH-dependent fashion. At acidic pH values, the fluorophores were almost completely unquenched, while at basic pH values significant quenching (85–90%) was observed. The pH at which the transition occurred was dependent on the PS concentration and ranged from approximately pH 5 to 8. The quenching kinetics was slow at low Cu2+ concentrations and basic values pH (up to several hours), while the unquenching reaction was orders of magnitude more rapid upon lowering the pH. This was consistent with diffusion limited complex formation at basic pH, but rapid dissociation under acidic conditions. The tight binding of Cu2+ to PS may have physiological consequences under certain circumstances.
...
...
Other Fluorophores and PS Molecules
Finally, to ensure that quenching was specific to PS and general to a wide number of fluorophores, various negatively charged lipids and fluorophores were tested for pH-dependent quenching (see Table S2 for a summary of the fluorophores and lipids tested). All PS lipids tested (DLPS, DOPS, and DPPS) quenched lipid conjugated fluorophores in the presence of Cu2+, but no other negatively charged lipids tested (PG, PA, GM1, and cardiolipin) produced any significant quenching. Moreover, the quenching kinetics of DPPS was tested and found to be identical to that of DOPS within experimental error (Figure S8).
Fluorescence quenching was also monitored in the presence of DOPS and 800 pM Cu2+ for 1 mol% 16:12 tail group-labeled NBD PC, 16:12 tail group-labeled NBD PS, 1 mol% 18:1 head group-labeled NBD PS, 1 mol% rhodamine-DHPE, 2 mol% fluorescein-DHPE, 0.5 mol% bodipy-DHPE, as well as at TR-DHPE concentrations from 0.1 to 5 mol% (complete names of fluorophores provided in supporting information, Table S2). DOPS concentrations of 0, 5, and 15 mol% were employed. All systems tested showed the same quenching phenomenon. Moreover, the normalized Cu2+-PS quenching from 1.0 mol% TR-DHPE was found to be essentially identical with 0.1 mol%, as was the quenching of head group-labeled lipids and tail-labeled lipids. By contrast, fluorophores attached to membrane-bound proteins showed no Cu2+-PS quenching (Figure S9), presumably because the fluorophore was too distant from the Cu2+-PS complex for quenching to occur. Even a rhodamine labeled bactenecin derivative (Rh-AAARRWKIVVIRWRR, a membrane associated anti-microbial peptide, where the initial three alanines are ß-alanine and the C-terminus is amidated), showed almost no Cu2+-PS quenching, despite its small size and known ability to partition into lipid bilayers.41 Thus, Cu2+-PS quenching is highly specific to lipid-conjugated fluorophores, which presumably have the appropriate in-plane geometry with the Cu2+-PS complex to afford quenching.
DISCUSSION
The very tight 1:2 Cu2+-PS complex observed in this work may have a number of biological implications. Given the concentrations of PS (variable, but generally µM to low mM)1 and Cu+/Cu2+ (also variable, but ~100 µM is often noted in the literature)19 found in cells and the tight binding observed in this work, it seems reasonable that at least under some conditions Cu2+ could exist in 1:2 Cu2+-PS complexes in vivo. The distribution of both copper and PS in various cell and tissue types are often seen to roughly track one another, both being present in relatively high concentrations, for example, in human brain tissue.42,43 Thus, increased PS may serve to complex and neutralize otherwise reactive Cu2+ in tissues that experience high Cu2+ concentrations. This complexation ability may be particularly important in mitigating copper poisoning. Alternatively, PS may attract Cu2+ to tissues that require greater quantities of Cu2+, although this seems less likely as Cu+ should be the dominant species involved in copper ion transport.18 The 1:2 Cu2+-PS complex may also provide insight into observations that copper ions and PS both play roles in many biological processes, such as fibril formation in neurodegenerative diseases and wound healing.21,22
As noted above, PS is known to bind a number of different metal ions. Ca2+-PS interactions have been the most extensively studied. These interactions are generally believed to involve high µM to low mM range equilibrium dissociation constants.10–12 This interaction mediates a number of different protein-PS interactions, specifically the membrane binding of C2 domain proteins, annexin proteins, and ?-carboxyglutamic acid domain proteins such as prothrombin. Thus, it seems reasonable that the observed 1:2 Cu2+-PS complex might also be involved (interfere or aide) in PS-protein interactions even in the presence of trace Cu2+ concentrations.
In addition to other roles, Cu2+ may also be involved in oxidation reactions. However, the quenching of fluorophores observed in the present experiments was almost perfectly reversible as illustrated by Figure 6. As oxidation is largely observed at relatively high Cu2+ concentrations, it may be possible that at trace Cu2+ concentrations, 1:2 Cu2+-PS complexes help to mitigate Cu2+ mediated oxidation. On the other hand, at higher Cu2+ concentrations, the complex should become saturated and excess Cu2+ may mediate oxidation. This is at least consistent with the present studies in which the employment of Cu2+ in the µM regime in a microfluidic setup at neutral or basic pH, irreversibly quenched the fluorophores (Figure 6B). It should be noted, however, that the high Cu2+ concentrations required to saturate the 1:2 Cu2+-PS complexes are well outside the normal physiological range for common cells and tissues.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351004/#__ffn_sectitle
The increased use of Fenton systems for the treatment of contaminated waters and wastewaters necessitates the development of kinetic models capable of accurately simulating key species concentrations in order to optimize system performance and efficiency. In this work a reaction mechanism in which the hydroxyl radical is nominated to be the active oxidant in Fenton systems is used to describe the oxidation of formic acid (HCOOH) under a variety of experimental conditions. A kinetic model based on this reaction mechanism is shown to adequately describe results of experiments in which starting concentrations of H2O2 and HCOOH varied over 1 and 4 orders of magnitude, respectively, under both air-saturated and deaerated conditions. The intermediate generated during HCOOH oxidation was observed to increase oxidation efficiency, especially at high initial organic concentrations [relative to Fe(II)], by assisting in the redox cycling of iron. In the presence of oxygen, however, such improvement was attenuated through competition for the organic intermediates. While mechanistic analysis and associated kinetic modeling is invaluable in optimization of Fenton systems, a clear understanding of reaction byproducts and their reactivity toward other species in the system is critical for accurate simulations.
https://pubs.acs.org/doi/abs/10.1021/es048378a
IMC: MDSC, Macrophages, T-Cell
TIM: Tim1, Tim3, Tim4
TAM: Axl, Mer, Tyro-3
Others: CD300a, RAGE, BAI-1, Stabilin
If Phosphatidylserine gets exposed it will WITHOUT DISCRIMINATION affect and bind ALL above PS receptors at the SAME TIME thereby implementing a global/upstream/systemic strategy to suppress the Immune System from intervening in the Natural Cell Death cycle (apoptosis).
One can immediately see that binding only TIM-1 as does Celldex or TIM-3 as does Novartis, or Axl as does Genentech doesn't implement a GLOBAL approach but just disables ONE specific receptor from binding with PS.
PPHM's Bavituximab and new BetaBodies however CAPS PS itself thereby disabling it from binding with all 12 PS receptors at ones and hence avoid not only suppression by the immune system but also stimulates the immune system to activate (which is a requirement).
Therefor acquiring the patents of PPHM, that cover this broad global approach achieve several things:
- no 12 different drugs needed in I-O combination
- no 12 dosings needed (because all these types of receptors do NOT occur in the same amounts)
- no mine-field of clinical trials to test all these combo's with PD-1, PD-L1, CTLA-4, etc.
- next generation not needing the presence of blood already available
- much higher binding instance because Bavituximab binds the exposed PS on non-mobile cells and reduced amounts in micro vesicles while all others target receptors on immune system cells that move and would have to meet THEIR PS receptor compatible molecule (out of 12) to bind.
- NO T-Cell PS receptor ONLY binding involved (wanted or as side effect (see TIM-3).
- immune system suppression BLOCKING and immune system stimulation at the SAME time
- Immune Response against relapse possible because of that and ONLY because of that.
Additionally other measures are possible. One can try to give transfusions to REMOVE floating PS from the blood stream WITHOUT ANY HARM DONE and so doing lower the amount of PS! One can not do that to the Immune-Cell holding the above mentioned PS Receptors because those cells are NEEDED.
So personally, while I agree that CEO King said that PPHM does not own the complete PS field, I think PPHM holds the patents to the ONLY strategy that can GUARANTEE that a PS molecule, when CAPPED, is disabled for ALL PS receptors at the same time and that wit ONE SINGLE drug to add to a combo.
Furthermore this works for Oncology, Inflamations/Infections, Viral, Surgery/Injury and actually in ALL CASES where a cell exposes PS while NOT due to the natural cell death cycle and where it mistakenly has the side-effect of suppressing the immune system.
PPHM holds all those patents.
