CEO Roger Lias has already proven he can not be trusted by making a mere mocking of the certified letters
He has been part of this staged act of performance and maybe he figured some of us did not know some Bavituximab patients
Remember....this is all about sabotage against PS Targeting and delaying the entire platform, which may have just included not stopping at anything and paying off researchers in various to silence them seems the plan. I still don't blame fully the prior BOD, because there could have been other ones to blame for things..
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But where bavituximab really begins to shine is when it’s used in combination with conventional cancer chemo-therapeutic drugs and irradiation. The drugs and the radiation cause the generation of highly-reactive substances, called reactive-oxygen species & free radicals, and what happens is that these highly-reactive chemicals again modify the structure of the external surface of the cancer blood vessels, and where they do so, flipping of more and more PS molecules to the outer surface of the tumor vessel occurs. And that’s then followed with the recruitment of more bavituximab and an increased assault by the white blood cells. And this is a real live view of endothelial cells as they appear under the microscope… After adding a cancer chemo to these cells, you begin to see flipping of PS to the outer surface of the cells, and that then gets bound by bavituximab, shown in green. So everywhere you see green is bavituximab beginning to bind to that exposed PS on the endothelial cells. And by 16 hrs, most of the cells have PS on their surface, to which bavituximab subsequently binds, and by 24 hrs all cells are positive for PS and binding. The same is true for tumors in mice. In an untreated mouse, 35% of the vessels will have PS on the external surface. If you treat that mouse with a single injection of Docetaxal, which is a very commonly-used and important cancer chemo-therapeutic drug particularly used in the treatment of breast cancer – that single treatment elevates the % of positive vessels to 60%. For a single treatment of Doxirubitin (DOX), 70% are positive. With Cisplatin, it’s about the same. And, if you irradiate the tumor, 80% of the vessels become positive. So you’re expanding the target for attack by white blood cells. This is an experiment showing you that bavituximab + chemo almost completely suppressed breast cancer growth in mice. So, in this experiment human breast cancer cells were implanted into mice and they grow progressively. If you treat with bavituximab, tumor growth is suppressed by 60%. With Docetaxal, it’s suppressed by about 65%. But the difference, of course, is that Docetaxal is extremely toxic, whereas there is no toxicity associated wit the bavituximab treatment. But most importantly, you can see that the combination treatment is almost completely suppressing tumor growth. And the combination is effective in treating drug-resistant cancer. Here, treatment of mice with drug-resistant cancer, extends their survival time by more than 2-fold. And that’s important, because cancers constantly mutate to become resistant to the drugs that are being used against them. But despite that resistance, the combination still works because it’s targeting the tumor vasculature, not the drug-resistant tumor cells themselves – a very important distinction. And here we looked at bavituximab in combination with Gemcitabine and its ability to suppress the growth of pancreatic tumors in mice – you can see the combo treatment has suppressed tumor growth by 90%. Furthermore, it prevents metastases spreading from the pancreatic tumor to the liver, a common site for metastases in man, and there’s complete prevention of liver metastases in animals treated with this combination of drugs.
So my conclusions for bavituximab as an anti-tumor agent are that it homes specifically to tumor blood vessels and induces white blood cells to attack the tumor. It enhances the effectiveness of cancer drugs and irradiation without contributing toxicity. And, Phase I clinical trials are underway.
We’re constantly striving to make better use of the PS platform for drug development, and we’re particularly pursuing other drugs that might be used to target PS or related phospholipids in different ways. So, a program is underway with Affitech in Norway to develop new human anti-PS antibodies that may recognize PS in a different way and maybe have different outcomes in terms of therapy. And they also recognize PE (Phosphatidylethanolamine) – this turns out to be another lipid that is also inside cancer blood vessels and gets exposed on the outer surfaces of those blood vessels in very much the same way as does PS. Secondly, we’re exploring the possibility of Imaging Tumors in people by targeting or imaging the tumor vasculature – and there we’re trying to identify tumors that are not visible by other diagnostic means. And, we’re also working hard to produce Anti-PS Cytokine Fusion Proteins. Let me fill in a few details… This is a rat with a prostate tumor here. The rat has been injected with bavituximab linked to an imaging isotope, 724-Arsenic, and you can see that the bavituximab has localized to this tumor tissue here… It’s a very nice, clean image – I would say an unusually clean image obtained using this Anti-PS Imaging technology. With the Fusion Proteins, what we’ve done is we’ve taken the genes that encode the Anti-PS antibody, here it is, the Y-shaped protein, and we’ve linked those genes to other genes that encode defensive proteins that induce greater attack of tumor blood vessels. The proteins we’ve looked at and have linked to our antibody are IL-2 (Interlukin-2), which activates white blood cells defense cells to give even stronger attack of tumor blood vessels. We’ve also linked Interferon to the antibody to give direct inhibition of tumor cell division, to create a drug that both targets the tumor vasculature and the tumor cells themselves. Also, a big attraction of Interferon is that they have anti-viral activity, so an Anti-PS/Interferon Fusion Protein is an exciting proposition for the treatment of viral diseases. This is showing you that the fusion proteins are actually working rather nicely – a combination treatment of the 2 fusion proteins I just showed suppresses the growth of Lymphoma, a cancer of the lymph glands, in mice by 93%, and of skin cancer, Melanoma, by 83%.
II. BAVITUXIMAB AV: I’m going to finish off by going to the 2nd use of the bavituximab antibody, and that is to describe its anti-viral properties. This is a host cell, very much a typical cell as we would have throughout our bodies. This cell is about to be infected by this enveloped virus here. The virus has a nuclear capsid, there it is in the center of the virus, and that’s where the genetic information of the virus is contained. The virus nuclear capsid is surrounded by a membrane which is called the viral envelope. Note that the uninfected host cell has an asymmetric outer membrane; the PS (shown in green) is confined to the inner surface of the cell membrane. So in a typical viral replication cycle, the virus will bind to the cell it’s infecting, it will get taken in, and then the viral nuclear capsid gets injected into the cytoplasm of the cell. And the genetic information makes its way to the nucleus, where it’s replicated, and you then get new viral nuclear capsids forming on the outside of the cell. What you get at this point is flipping of PS from the inside to the outside surface of the virally-infected cell. So, as the virus, or the nuclear capsid egresses, it gets wrapped up in randomized host the cell membrane, with PS on its external surface. And because the virus has no means to re-internalize that PS, it stays on the external surface. This thinking suggested to us that Anti-PS antibodies might be used as anti-viral agents for 2 reasons. First, that the antibody might bind to the outer surface of the viral envelope, leading to clearing of the virus from the bloodstream. Second, that bavituximab would bind to PS on outside surface of virally-infected cells, leading white blood cells to attack the virally-infected cells. And it was a very exciting proposition, because it has a number of advantages that other forms of AV therapy lack. What this approach has is the potential for broad-spectrum activity against enveloped viruses of mult. types. And that means it could be administered after exposure to virus in a bioterrorism setting before the identity of the virus is known. And lastly, it should avoid viral resistance because it targets phospholipids on the virus and the infected cells that are independent of the viral genome. So, the virus might mutate to become drug-resistant, but it shouldn’t be able to affect the distribution of the phospholipids which come from the host cell, not from the virus.
We first looked to see if bavituximab binds to different enveloped viruses. We looked at 13 diff. enveloped viruses belonging to 6 diff. virus families. We looked at the Pichinde virus, which is a model for Lassa fever in man. We looked at the Bovine Viral Diarrhea virus, which models HepC. We looked at Varicella-Zoster. We looked at Influenza A + B, Avian Influenza (H5N1), Bovine Parainfluenza, Measles, RSV. And then we looked at the immunodeficiency viruses, FIV, HIV1, HIV2, SIV – it’s the HIV1+2 viruses that cause AIDS in man. What we found was that bavituximab indeed binds to viruses of all 13 types that we analyzed. And that virus binding is specific, because we went to 6 diff. viruses that lack an envelope so they can’t have PS, they of course do not bind to bavituximab, as you would expect. So indeed it seems true that bavituximab has broad-spectrum binding to enveloped viruses of diff. types. Next we asked, is it possible that bavituximab does bind to infected cells that have just been infected by virus? To do that, we looked at cells that had just been infected with Influenza A, Vaccinia, HIV, Pichinde, and in all cases infection with the virus induced PS exposure and bavituximab binding. Again, that was specific – it was not seen with control antibodies. And when we treated guinea pigs who had advanced Lassa Fever-related viral infection, 50% of the guinea pigs went on to be permanently disease-free responders, and were actually resistant to re-infection with the same virus – a remarkable result given the severity of the disease. Furthermore, bavituximab works in combination with an established AV drug, a very good AV drug called Ribavirin, and you can see the 2 drugs, because they act in totally diff. ways, have additive activity. So the purple line shows that animals receiving this combination do better than animals receiving the indiv. drugs. And that’s important because in a patient setting, of course, they would receive both therapies. We looked at mice infected with murine cytomegalovirus virus (CMV), and those mice were treated with 3G4, which is the mouse version of bavituximab, and all animals treated survived, as compared with only 20% or so in the groups receiving control antibodies or various other control substances.
We spent the last year doing a lot of work trying to unravel the mechanisms on how bavituximab works – the better we understand the mechanisms, the better we can make improvements in the design of our drugs and their scheduling to make the best use of those drugs. It turns out that there are 2 major mechanisms by which bavituximab exerts its AV effects. The 1st mechanism is that it causes clearance of free virus from the bloodstream. Here you see virus in the bloodstream – all of these are virions, and what happens is that when bavituximab is injected, it binds to the virus and then a white blood cell binds to the antibody-coated virus and sweeps it out of the bloodstream, leaving less virus available other important normal tissues. And the 2nd mechanism is bavituximab enables while blood cells to kill virus-infected cells. What happens here is that the bavituximab binds to PS on cells that have just become infected by a virus, and this sends signals to white blood cells to attack the freshly-infected cell and destroy it. And so, the mature virus does not get out of the cell in order for it to be able to infect other normal tissues. Those 2 mechanisms are what we believe explain the AV effects of bavituximab.
In conclusion, for bavituximab as an AV agent, it shows broad-spectrum binding to enveloped viruses and virally-infected cells. Treatment of animals lethally infected with Pichinde virus or murine CMV results in 50-100% survival, the AV effects in the Pichinde virus model are due to killing of infected cells and clearance of virus. And, lastly, AV strategies directed against host cell phospholipids show promise as a broad-spectrum AV treatment. This work was done at Peregrine Pharmaceuticals, in collab. with my lab at UTSW/Dallas, with the collab. of Avid Bioservices, The Southern Research Institute (SRI), and ImQuest BioSciences Inc. Ladies & gentlemen, thank you very much.”
Thorpe Slide46: COLLABORATORS • 12 researchers from UTSW (Xianming Huang, Jin He, Melina Soares, Sophia Ran, Troy Luster, Linda Watkins, Gustavo Barbero, Sameer Syed, LaShe’ Ingram, Helen Arizpe, Dan Ye, Janie Iglehart) • 5 people from Peregrine (Aimes, Chang, King, Parseghian, Shan) • AVID Bioservices • Southern Research Institute (Thomas Rowe [see http://tinyurl.com/yymnje ] & Barbara Taggart) • ImQuest BioSciences Inc. http://www.imquest.com
