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Filed in 9/04.
How does this stack up against what we have been awarded or applied for? I realize that AnnexinV (now called AxA5??*) is a protein but not a MAB, but I wonder if we will have to deal with these guys.
*http://www.med.ub.es/MIMMUN/FORUM/ANNEXIN.HTM
I saw those, but when I saw "Vatuximab," I turned away thinking it wasn't us. "Vatuximab" does not appear on the PPHM website, and I do not recall it. I have found it in some documents dating to 2004.
Did "Vatuximab" have a short career as the in-house name for what, last year or early this year, was given the USAN name "Bavituximab?"
Another 3G4 research project from DoD:
http://cdmrp.army.mil/scripts/get_item.asp?item=abstract&type=technical&log_no=BC052598
"Mycobacterium tuberculosis, the causative agent of pulmonary tuberculosis, infects one-third of the world’s population (1). It accounts for more deaths each year than any other single infectious bacteria (2). Its ability to survive and replicate in the host macrophage is critical to its pathogenesis, emphasizing a need for a clearer understanding of its interactions with the host macrophage. In vitro experimental models have demonstrated that M. tuberculosis infection causes apoptosis of host macrophages. This has been demonstrated by the detection of annexin V binding to surface-exposed phosphatidylserine early after infection with M. tuberculosis."
http://www.jimmunol.org/cgi/content/full/170/1/430
I have in the past put a couple on iggy, and they have remained so-- when I click on their names it still sez "unignore this poster," but it is no longer a live link.
Inflation, I guess . . . .
Has the ignore button been deactivated for free users?
"Also is it just a test tube phenomenon (in vitro) and not an actual prolongation of the PTT in vivo[?]"
What is your guess, and why?
My earlier posts about exposed PS on activate platelets appear to have addressed correctly only one of two reasons for the increase in pro-time and APTT.
"A prolonged aPTT means that clotting is taking longer to occur than expected and may be caused by a variety of factors (see the list below). Often, this suggests that there may be a coagulation factor deficiency or a specific or nonspecific inhibitor affecting the body’s clotting ability. (snip) Inhibitors may be antibodies that specifically target certain coagulation factors, such as Factor VIII antibodies, or they may be non specific inhibitors, such as lupus antibodies and anticardiolipin antibodies that bind to chemicals called phospholipids found on the surface of platelets. Since phospholipids assist in the clotting process, and since the aPTT test reagents (chemicals used to run the tests) contain phospholipids, such antibodies may prolong the aPTT even though they are usually associated with thrombosis instead of bleeding.
http://www.labtestsonline.org/understanding/analytes/aptt/test.html
So, not only do we have to assume that Bavi will bind with the PS displayed on the activated platelets (just as ACL and lupus antibodies can), delaying the cascade and reducing its magnitude of its expression, but it appears that Bavi will also bind to phoshpolipids in the test reagents themselves, just as ACL and lupus antibodies do.
Here is the BBC squib:
"Treatment to Neutralize All Flu"
http://news.bbc.co.uk/2/hi/health/5404184.stm
"Scientists say they are developing an entirely new way of providing instant protection against flu.
In preliminary tests, it was found to protect animals against various strains of the virus - and may also protect against future pandemic strains.
University of Warwick researchers used a flu virus naturally stripped of some genetic material to compete with other invading flu viruses.
This slowed the rate of infection so much the body could fight it off.
In effect, the invading virus became its own vaccine by triggering an immune response sufficiently powerful to neutralise it before it could gain a strong enough foothold."
Here is the result of a quick medline search:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&l...
"Defective interfering (DI) virus RNAs result from major deletions in full-length viral RNAs that occur spontaneously during de novo RNA synthesis. These RNAs are packaged into virions that are by definition non-infectious, and are delivered to cells normally targeted by the virion. DI RNAs can only replicate with the aid of a coinfecting infectious helper virus, but the small size of DI RNA allows more copies of it to be made than of its full-length counterpart, so the cell produces defective virions in place of infectious progeny. In line with this scenario, the expected lethal disease in an influenza A virus-mouse model is made subclinical by administration of DI virus, but animals develop solid immunity to the infecting virus. Hence DI virus has been called an 'interfering vaccine'. Because interfering vaccine acts intracellularly and at a molecular level, it should be effective against all influenza A viruses regardless of subtype. Here we have used the ferret, widely acknowledged as the best model for human influenza. We show that an interfering vaccine with defective RNAs from an H3N8 virus almost completely abolished clinical disease caused by A/Sydney/5/97 (H3N2), with abrogation of fever and significant reductions in clinical signs of illness. Animals recovered fully and were solidly immune to reinfection, in line with the view that treatment converts the otherwise virulent disease into a subclinical and immunizing infection."
This sounds like something with some staying power.
"I am almost certain that the APTT and PT do not measure platelet function."
They don't measure it directly, I agree.
Primary hemostasis is the first event in clotting, where the first platelets to arrive adhere to collagen in injured tissue.
The first platelets then become activated, and activate others. Activated platelets expose PS, which is required by at least two of the 12 or 14 coagulation factors to perform their role in the coagulation cascade.
To the extent Bavi covers exposed PS, everything is slowed down, as reflected in the increased pro-time and APTT.
This is my simple take on it. I think the increase in the times is due not to Bavi interfering in any of the steps in the cascade, but to Bavi hiding the PS, which impairs the entire process of secondary hemostasis (the cascade as a whole). Therefore I do not fault PPHM for not doing what you suggest they should have done. And I am not sure what "metabolic problem" you are referring to, unless it is the slight increase in the times . . . .
But I could be wrong, it's happened before.
http://www.medscape.com/viewarticle/468098_2 (esp. last graf)
http://en.wikipedia.org/wiki/Coagulation
WHY ARE SO MANY MESSAGES MISSING FROM THE MAIN LIST OF MESSAGES, INCLUDING THE ONE (9053) TO WHICH THIS MESSAGE IS RESPONDING?
The reason the increase in pro-time and APPT was "expected" is that activated platelets display PS on their exteriors.
"Other studies looking at platelet activation showed that circulating unactivated platelets had low levels of phosphatidylserine on the outer leaflet of their membranes[footnote moitted]. However, when platelets were activated, the amount of phosphatidylserine on the outer leaflets increased dramatically from {approx} 2% of the phospholipid content to as much as 12%."
http://atvb.ahajournals.org/cgi/content/full/22/9/1381
I don't think that protecting patents is a duty left solely to the licensee, even an exclusive licensee. Otherwise, lightly-capitalized firms couldn't get licenses to important patents.
In this case, the assignee of the patents is sitting on billions.
I think the possibility of developing some form of autoimmunity or loss of immune tolerance, or other immune-system complication, cannot be ruled out until larger numbers of humans receive the drug and are monitored for several to many months afterward. IMO, lack of a definitive showing of "no problem" is the main reason the stock is still somewhat risky.
Laughably, you stated: "So once the virus is inside a cell, bavituximab can't touch it."
Peregrine begs to differ, and I am not sure Jazz' sly response to you highlighted this fact sufficiently.
Bavituximab (formerly known as Tarvacin) is a monoclonal antibody that binds to a basic component of the cell structure called an aminophospholipid that is exposed on the surface of cells only when they are infected with certain viruses or when they are malignant.
After binding to these infected cells, the drug alerts the body’s immune system to attack the infected cells.
http://www.peregrineinc.com/content.php?mi=Mzg=
I am of average or above-average intelligence, I did not understand your post. Can you clarify?
Adenosine's Role in Tumor Cell Immune Escape
http://www.nih.gov/news/pr/aug2006/nci-14a.htm
"pump based on the square footage"
In fairness, this decription was in response to a "BFD" attempt at minimizing the event.
I haven't felt any tremors.
Oral presentation at The Liver Meeting® 2006
http://biz.yahoo.com/prnews/060816/law044.html?.v=72
Effica[c]y is the word used by PPHM.
I distinctly remember a tiresome series of posts here disputing that any efficacy was shown. Has that all died down?
How much has changed since
http://www.investorshub.com/boards/read_msg.asp?message_id=8051402
??
Why, in my message number 7506, does IHUB state that it is "in reply to a deleted message," when BOT's 7505, to which I replied, is not deleted?
"Analysts do not get excited about the HIV market on a stand-alone basis"
That does not seem reasonable, does it? How many HIV+ people are there, scores of millions, right?
I saw the names but I think it is too indirect, plus the purpose of the grants to Duke-Montefiori and Duke-Haynes don't sound PPHM-related. BWDIK? That's why I threw it up on the wall here.
"censorship mind"? Did I censor you?
Just because I don't believe the US Navy shot down the 747 off LI, or that PPHM mgmt will contrive a bogus study result as you smarmily suggested, that doesn't make me a censor.
If you are stupid enough hold the stock in light of your suggestion, you need financial (and other) advice. That's all I saud. You are on ignore.
Is that censorship too, boyo?
"and then devise a flawed P3 trial that will allow it to be torpedoed by the revolving doors of the FDA in return for some form of 'equity' from BP"
Please tell me what your interest in this stock is. If you truly entertain the notion quoted above and don't immdeiately dump all shares you have, you should get someone else to handle your money.
"Good Luck, I will pass on using your board from here on out."
If I believed it, I'd say, "TYVM."
DELETE
FWIW "SRI International" used be called the "Stanford Research Institute."
http://en.wikipedia.org/wiki/Stanford_Research_Institute
People on other bds are saying that Double U Master Fund LP (the people behind the last PIPE) dumped their shares. This was to be expected, apparently-- they are fast money, not LTBH, and they made about $2MM on an investment of $13MM for about a week. I guess we should be glad they chose this time to sell, avoiding panicked reactions.
I don't know whether PPHM's promises to UU are still in effect, and I don't know if the answer is even important.
Anything is possible, of course, but I think the answer to your question is that the names of licensees do not appear on patents in the USPTO. And why should it?
"You think they will let a big Pharma steal our baby and hide it in a shoe box so they can keep using their outdated medicines."
Well, without making an overtly political post, I guess it depends on who you think may have the government in its pocket.
"That's the master phospholipid platform cancer patent."
Here's the "Field of Invention" from the patent:
"The present invention relates generally to the fields of blood vessels and tumor biology. More particularly, it embodies the surprising findings that aminophospholipids, such as phosphatidylserine and phosphatidylethanolamine, are accessible, stable and specific markers of tumor vasculature. The invention thus provides therapeutic constructs and conjugates that bind to aminophospholipids for use in delivering toxins and coagulants to tumor blood vessels and for inducing thrombosis and tumor regression."
I may be wrong, but IMO this patent does not include the targeting of phospholipid markers other than those found in the linings of blood vessels.
This is probably only on my mind because of the recent posts on TM-610, a protein targeting phospholipids on the walls of the actual tumor cells, and that is apparently not delivered via the bloodstream.
But I agree it is a dandy.
I did a little looking:
http://www.transmolecular.com/publications.htm
"Introduction: I-TM-601 is radiopharmaceutical that combines a 36-amino acid peptide, called chlorotoxin (designated TM-601), derived from scorpion venom with a medicinal isotope of iodine (I). TM-601 binds a receptor found on the surface of tumor cells, which is not found on normal cells. TM-601 binds many solid tumors types including glioma, breast, lung, prostate, and melanoma. No toxicities have been observed with the administration of TM-601 to rodents or primates. Its small size permits it to diffuse through tissues and across the blood brain barrier. A single dose of I-TM-601 administered intracranially to human xenografted mouse models of glioma has been shown to extend survival . . . ."
So they say it crosses BBB; but the tumor does appear to have been scooped: TM-601 is given by a "ventricular access device (VAD) placed in the tumor cavity at the time of resection. 14 to 28 days later, a single dose of a 2 ml solution of I-131-TM-601 is administered over a five min period via the VAD."
http://www.transmolecular.com/publications.htm
Here's to "RSVP" therapy- "Radioactive Scorpion Venom Protein" (no kidding) apparently targeting the exposed phospholipids on cancerous glial cells.
http://www.transmolecular.com/productpipeline.htm#
I got this in an EMail:
"At this week's
meeting of the Health Physics Society in Providence, researchers
will describe how they have helped establish the safety of a
surprising new treatment for an aggressive, essentially incurable
malignant cancer called high-grade brain glioma, diagnosed in over 17,000 people in the US every year. The treatment is based on the discovery that the venom in the yellow Israeli scorpion contains a protein that binds selectively to the glioma cells. The procedure uses a compound called TM-601, a synthetic version of the venom protein attached to a radioactive substance called I-131 that kills the glioma cells. When injected into the bloodstream, the radioactive scorpion venom protein travels to the brain and attaches to the glioma cells, with the I-131 releasing radiation that kills the cells."
You can see the whole storyette at
http://www.aip.org/pnu/2006/split/782-1.html/
Also this, which sez not PS but a phophatidyinositol molecule of some sort.
"Background: Tumor formation requires altered motility of transforming cells to invade surrounding tissues. This altered cellular motility involves formation of lamellipodia, protrusions of the plasma membrane at the leading edge of the cell. Recent studies establish a role for phosphatidylinositol-3-kinase (PI3K) and the PI3K/Akt pathway in initiation of membrane ruffling and actin stress fiber formation, events necessary for lamellipodia formation. PI3K regulates the membrane phospholipids PI(4,5)P2 and PI(3,4,5)P3 that serve pivotal roles in cell signaling, and when deregulated, contribute to tumor formation. Methods: We investigated the mechanism of action of TM-601, a synthetic peptide derivative of scorpion venom, in human cancer cells. Multiple established human cancer cell lines were used in these studies, including solid tumor (glioblastoma, prostate, breast, lung, melanoma, colon) and hematologic tumor cell lines (lymphoma, leukemia, myeloma). Histochemical staining, FACS analysis, and in vitro binding assays were used to characterize TM-601 binding, identify specific intracellular targets, and investigate downstream effects. Results: TM-601 bound all cancer cell lines tested and histological staining localized binding to the lamellipodia of cancer cells. Using in vitro binding assays, we identified phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), as the cellular target of TM-601. Additionally, our results indicated multiple downstream consequences of TM-601 binding to PI(4,5)P2, including reduced activity of PI3Kγ, increased activity of GSK3β, and inhibition of DNA synthesis. Conclusions: TM-601 is a novel 36 amino-acid peptide that targets human cancer cells via a phosphatidylinositol phosphate resulting in altered activity of the PI3K/Akt signal transduction pathway. 131I-TM-601 is currently in Phase II clinical development for the treatment of adult recurrent glioma."
http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb6...
If this works I guess we'll see how good our patents are.
Dunno a thing about ANA 975 or its MOA, but could their careful repetition of the phrase "intense immune activity" be a code word for autoimmunity?
NYT on how Toxoplasma Gondii redirects immune system:
http://www.nytimes.com/2006/06/20/science/20toxo.html
FWIW-
"Pursuant to the agreement and subject to certain conditions, Peregrine Pharmaceuticals has agreed not to offer or sell its common stock in any private placements at a price below $2.50 per share during the remainder of the calendar year."
I hope that "normal," non-disease-related apoptosis occurring at low levels does not involve any essential processes which would be negatively affected by Bavi's appearance on the PS. It doesn't look like there are any immediate problems, but the fact that the low-level "normal" apoptosis poses no problem in the absence of Bavi does not prove that there will be no problem in the presence of Bavi.
Because evolution has conserved this non-inflammatory phagocytosis pathway that is closed by Bavi, it seems at least possible that some processes or mechanisms have also evolved that depend on this pathway and which might be affected by Bavi's redirection (perhaps causing a slow accumulation of some bad fragments, or a gradual rise in a signalling molecule that is meant to remain at low levels). Probably no big deal, but still, I am glad of the long-term aspects of these studies.
Someone just posted something suggesting that there may be a maximum desirable Bavi titer. I have been wondering for a while whether too much Bavi may result in a lot of unemployed molecules, looking for PS in all the wrong places. If this should prove to be correct, maybe there is a marker or a simple test.
And when we can conclude that there are no apoptotic cell types displaying PS that the body NEEDS to continue to phagocytize with little or no inflammation (because the new Bavi-promoted inflammatory pathway would lead to some kind of serious problem) we will all feel better.