north and jess, thanks. Your posts about new findings of Bavi plus Prima-1 provided an interesting chase through the literature to learn more about Prima-1. It apparently helps the cell reverse a mutation at the p53 locus, a mutation that inhibits the cell's apoptosis ability, jada. Prima-1 is known to act alone and synergistically with chemotherapeutic agents to inhibit tumor cell proliferation. Nice article.

thanks jess, interesting how much we are learning as we go along, and how we are living the manifestations of the law of unintended consequences. The science of cell surface -PS is ballooning as we watch, and PPHM is in pre-eminent position to apply it to humans as therapy.

jessme, ms kso one smart gal. PPHM thoughts: Optimism after the stock split. Same share price now. Didn't crater. A better base. What changed after the split? Interestingly, nothing. Price depends on news, as does share trade-volume. Every indication is that significant news is forthcoming this year, and if good enough to indicate marketability, the stock price skyrockets. The groundwork has been carefully prepared.
My concern about PPHM does not relate at all to the technology. Results won't be cures, but good enough to go to market with a viable treatment option. It is unfortunate that the human trials were "handicapped" out of deference for losers still in the race, and that PPHM must test unarmed "naked" Bavi when Bavi could also be packing a walloping payload of cancercidal agents and still stimulating patient's [mostly thrashed] immmune systems. Trial results for naked bavi as an immune stimulant do not relate in any way to what MABs are mostly about, or what Bavi was developed for. It's the gov'mt. Go figure. The biggest thing PPHM stockholders have to fear is the government and politics, undeniably an increasingly large factor. If the People's Army of China is working on Cotara, and the US military is looking at Bavi, beware of...uh...transparency. 50k shares traded in a day? Nonsensical. What reasonable person would believe it? 59K shares a day is about what several individual reading this board could trade each day on their own. Still, slow accumulation is likely to be rewarded, and if not us, our children? grandchildren? PPHM stock is still a great stocking stuffer.

errata: 86 doses instead of 868

charlie3: side-effect profile appears good--acceptable. 6 serious adverse events were observed in 5 patients/26 in 868 doses, with 1 drug-related pulmonary embolism at the 3 mg/kg (highest) dose. The most common adverse events in >=15% of patients were: nausea, fatigue; headache, constipation, dizziness cough, dyspnea, anemia, and chest pain. Re. the pulmonary embolism, remember that blood clots are part and parcel of cancers since they tend to be "pro-thrombotic," and it is difficult to imagine an effective anti-cancer agent without side-effects. Because of sample size the side-effect profile might move either direction still, so...just so there isn't serious hair loss!

charlie 3, agree with 1st half of post, that the default assumption is all employee/consultants are still in their places with bright shining faces, but do not agree with last part of the post since past star consultants have come and gone through the revolving door without notice. The survival numbers are what count in the end. Fascinating narrative, this. I'm still aboard and accumulating.

cheynew, good article, thanks. I agree. Those who think radioisotope diagnostics and therapeutics are "on the way out" are simply not correct.

cj, absolutely awesome, huh. And thanks for all.

pphmtoolong, seems that the article is another one dealing with blocking retrovirus ENTRY into cells via the glycoprotein envelope docking site mentioned here a couple times before, rather than the lipoprotein membrane sites that Bavi targets in order to block viral envelope formation on exit from the infected cell, and non-specific immunological boost.

cheynew, interesting chasing that lead down on GBM, and finding out about Exelixis, a biotech that partners with Bristol-Meyers mostly, with a clutch of pipeline MAB products in trials, some of which directly compete with PPHM, such as those being tested for GBM and an VEGF2 MAB. Good to take a look at the competition once in a while. Amazing what baskets full of money can accomplish.

disco, see post 47733. The conference you mention appears to be all about the same (or similar) efforts mentioned in 47733, targeting cell envelope GLYCOprotein docking sites to prevent virus entry rather than LIPOprotein docking sites used by Bavi to interfere with viral exit strategy and enhance immune response. My take on it is that Haynes is orchestrating a dual strategy, using both. Should be an interesting conference, as you said, but not directly related to Bavi or PPHM.

Until 2000: The investigational human monoclonal antibodies (hMAb) M9, 2F5, and 2G12 recognize cell surface docking sites that are mostly glycoproteins. "Glyco-" (glycogen=starch=carbohydrate) and protein. Bavituximab targets a fat-laden docking site. The subject antibodies are thought to act by inhibiting the attachment and entry of HIV viruses into susceptible cells. Bavituximab action interferes with viral capsule formation at exit from the cell, and encourages enhanced immune response. Sounds like the two groups might be synergistic. Also, I am sure that there is intense efforts to engineer a smaller, more streamlined Bavi. All the above is mostly guesswork. Don't take it to the bank. I am still learning too!

golfho and threes, thanks. A few thoughts: it is the stock "run-up" price during the approval process that nets the most bang for the buck, not necessarily the final approval as such. I agree with threes that the time frame will vary so much, as will the price tag, that accurate predictions are difficult. IMO the chances of a "bust" on all products in PPHM pipeline is essentially nil. Regarding biosimilars: they are not (bio)generics, but near-copies of existing biologic medications made with a different cell lines and different manufacturing and purification process, thus final products are not identical to the precedent. The excitement generated at PPHM for biosimilars most likely relates to 2C3, a better Avastin because it is more specific. 2C3 IMO is a textbook description of a biosimilar that should be ushered through FDA regulatory channels at mach speed (or at least close to that)!

co3aii, my take-away from the Haynes interim report, without much study or cross-referencing, is that the collaboration remains alive and well between Haynes group and Thorpe group. All investigators are exploring new avenues that have recently opened up around their boulevards of expertise. Specifically, the observation of B-cell tolerance for HIV is being explored by several strategies, and Thorpe is looking taking advantage of the observation that patients with auto-immune disease are more resistant to HIV infection and/or full expression of AIDS. We know that some with auto-immune disease also have increased levels of anti-PS. We also know that anti-PS, or Bavi at least, does not deal a knock-out blow, but is partially effective. Haynes and others are looking at immunological methods of changing tolerant B-cells to intolerant, and also at how to amplify effective anti-HIV B-cells that are suppressed or rendered ineffective. They are aiming at an over-all strategy of an anti-viral vaccine combined with anti-PS immunological adjunct(s) such as Bavi. We know effective B lymphocytes are produced, but destroyed by the body before they can reach effective numbers. Only a thought....Someone tell me if I need to revisit it. Virology and immunology are not my fields!

mostly 'cuz its at the Waldorf-Astoria, NYC.

firefox, yes, nice. thanks

Come on gang, don't feel badly about doubting UMASS, or about hoping he is real. It's not what he says that shoots him in the foot, but how he says it. UMass will not die or go away if discredited, but like ocean water evaporates into clouds, and then reappears as rain, he will come again but with yet another name.

chey,research on Stason,Inc., suggests that the connection might be related to storage, manufacturing, and transportation of I131, a rather specialized field. Stason strikes me as being real--a niche player with expertise in regional blood-flow measurements, micro-spherule drug delivery systems, and know-how in the FarEast. Seems like a strategic alliance to me.

Clearwater, which one? You don't believe BigPharma lets small biotechs do 80% of the research on drugs for cheap, scraping by and begging with hat in hand, and then buy them for pennies on the dollar? What part of it don't you believe? Medarex was one of the leading biotech companies focused on MABs for cancer, autoimmune diseases and infectious diseases.The company had three Phase II and Phase III drugs for metastatic melanoma ,lung cancer and prostate cancer. Bristol Myers (BMY) was an early player in the monoclonal Ab therapy area when it partnered Imclone in developing Erbitux. Rumors of a BMY Medarex buyout had been around for months. I paid as much as $16/share for MEDX at one time, and later Bristol Myers bought Medarex (MEDX) for $16/share, a 90% premium over the THEN current market price of $8.40. Don't see any similarity? Would you be happy with a 90% premium over current share price? Ever gone to an auction where you know someone has their eye on an item and you know they are not going to be outbid? Couldn't happen here--that a mega-company is working behind the scenes with PPHM? Fantasy,huh. Remember the Roach and those folks who brought us Avastin. We'll see.

Industrial sabotage? Thoughts and speculation. Most interesting post recently IMO was about Affitech financial trouble, similar to PPHM's a few months ago. Are Roach [sic] fingers in both pies, Affitech and PPHM, a coincidence? Affitech will survive, but its stockholders will pay the same usurious rates to the money lenders that PPHM and other biotechs pay while company value rises.
One behind-the-scene scenario that makes sense to me,re. PPHM stock price, is an BP industry "whisper" saying that PPHM is hands- off...already spoken for. The finishing touches of product research, i.e., later phase trials, will be "barely financed" by nameless and faceless investors; stock rallies killed by the same; all sothe stock is relatively cheap before the company is sold at pennies on real dollar value. How long will the news be bottled up? Look at Medarex and BMY's purchase of a great MAB, good MAB production facility, and a good pipeline. Not difficult to connect the dots.

Thanks Thales, an interesting read about Bristol-Meyers. I have held that stock for several years, buying at $22 ($24 now), so it has not been a home run. BMY is fortunate to have gotten out financially solvent after its venture into IMCL. I had Medarex stock and followed that company also, a PPHM-like MAB company with production capability, a terrific fully-humanized anti-EGF about to be released,and a good pipeline. BMY has cash. "Looking for deals" is a bit vague.

co3aii, the company's Lymphoseek is a system for mapping lymph node metastases using tecnetium-99, a short-lived gamma ray-emitting nuclear isomer of technetium used in nuclear medicine for many diagnostic tests. The system may be used during surgery to help surgeons determine extent of resection required. The company is now going after mapping of all solid tumors using various MABs which were not specified. I am not sure how much of a market there is for the product when the mapping via full-body scans may be done preoperatively with the same accuracy. However, neither is being done comprehensively at this point. I imagine that Bavi or another one of PPHMs MABs could be used for the process.

thales, thanks. Completely agree.

right dia. PPHM is on a roll...albeit a slow one. No slips. No reversals. Gradually improving the situation. Means to gradually continue buying imo. Good luck all.

Has anyone seen ANY publications out of China about Cotara efficacy, etc? Does anyone know if it is being used? Or how to find out? My literature search only turned up the one article 2007? about the low rate of allergic reaction to Cotara.

firefox, one strategy thought that occurred to me is PPHM's possible inability to control Cotara-like spread through Pacific rim from China. Suppose this deal could also be addressing that possibility?

jess, interesting question about why SuperGen relationship with PPHM was severed re. VEGF. After spending a few minutes researching, my sense of it is that it never was a particularly good fit. SuperGen is interested mostly in small molecule approaches to cancer using a super anti-tumor screening technique, and is working on anti-VEGF via small molecule signaling rather than MABs. Additionally, you probably recall that, "In July, 2009, Peregrine out-licensed exclusive worldwide rights to develop and commercialize products under their selective anti-VEGF intellectual property portfolio to Affitech A/S. This agreement would appear to take the two companies even farther apart on VEGF. There is some cross-over in cell signaling studies, but not in the form of finished product. Brekken's presentation to Lung Society (as a 2008 grant recipient)spelled out his plan to solve why lung cancers are so variable in resistance to VEGF by looking at genetic makeup of resistant and susceptible strains of lung cancer strains. Brekken said, "r84 is distinctive because it selectively blocks VEGF from binding to VEGF receptor 2 (VEGFR2), while non-selective agents such as Avastin block binding to both VEGFR2 and VEGF receptor 1 (VEGFR1). Selective anti-VEGF agents such as r84 may have safety and efficacy advantages over non-selective approaches. In addition, the fully human nature of the r84 antibody minimizes the risk of an immune response against the drug itself, thereby lessening the potential for immunological side effects and neutralization of the treatment effect. As a fully human antibody, r84 may also have better pharmacokinetic properties in patients. In November, 2009, results of preclinical studies using r84 were published in the journal PLoS One, demonstrating that r84 was as efficacious as Avastin®/bevacizumab and Sutent®/sunitinib in a preclinical model of cancer. The studies also showed that r84 limited the emergence of immunosuppression in preclinical cancer experiments..."

dia and sun, thanks. agreed.

sunstar, I don't think it's quite so simple as cutting off the blood supply to the cancer and it dies...but almost. We know that cancer cells may survive in an avascular environment, whether it is the necrotic core of tumor or the outer cells which are bathed and nourished simply by diffusion from body fluids.

firefox, thanks. I think we are in agreement, and I think I have a fair understand the "micro" MOA of Bavi, which is what I posted about the last couple days--chemokines and all that--and which I thought you posted that we should not get bogged down about.
I can't agree that the double-armed model works as well with one of the arms tied behind its back, so to speak. We know that VEGFs (Avastin) destroy tumor vasculature too, as does anti-PS, but it is the residual cancer cells that I think should also be addressed, especially in immunocompromised patients.

firefox, I watched the Thorpe video again and did not see this quote you printed: "One end of the Bavi MAb sticks to the PS. The other end of the Bavi MAb is called the FC Receptor and is wagging in the breeze as various white cells in the blood supply float buy. These white cells (in particular Macrophage and Natural Killer Cells) stick to the FC Receptor on Bavi and immediately cause a cytotoxic reaction that “attacks and destroys the tumor blood vessels”. Do you have a reference to that MOA, that macrophages stick to the FC Receptor? We need to use that FC receptor to carry a payload to kill residual tumor cells left over after the blood supply is cut off. Just a thought.

Firefox, thanks. Great summary. You're right, the original anti-tumor vessel mechanism of action is the key.

Moby,there's no question Bavi would bind to unknown metastases (as would Cotara if there is necrotic core, or DNA-histone to bind to), but what I don't understand is what the downside to that would be. It might prejudice progression data, but improve survival data. All conjecture.

so cj, my "take away" from the anti-PS blog information remains similar to a previous post in which I questioned the alignment of Duke and PPHM interests. Duke is interested in the mechanism of action of anti-PS antibodies so virologists can brew a vaccine that duplicates it.
They believe that one MOA of anti-PS is to cause the release of MIP chemicals from immune cells which "dock" on a specific cell receptor site CCR1-4 which is a site through which HIV enters the cell. Plugging that receptor site diminishes HIV entry.
How does this synch with another proposed MOA for Bavi which interferes with viral encapsulation?
An MIP vaccine?
No wonder PPHM management emphasis appears to be returning to cancer treatment. IMO "naked" Bavi's effect on the immune system is a CURIOSITY and frosting on the cake, and as such, is sumpin' we can leave to others. Bavi's construction was predicated on the need for, and use of, the second payload-bearing arm which could carry chemo or irradiation to the tumor directly so that normal tissue is not poisoned or irradiated in the treatment process. I say we get on with it.

Moby, whatcha mean man? "Isn't the risk there the same as what happened with TNT? Bavi taking a payload to some undiscovered cancer site within the body could derail a trial." I don't get your drift.

cj, thanks. Tony Moody, at Duke, used anti-PS MABs taken from auto-immune disease patients, and confirmed that [in a test tube] the Anti-PS MABs “neutralized” virus, or decreased viral cell entry, and the mechanism was via release of cell-synthesized chemical attractant compounds called “chemokines.” The specific chemokines, called MIP1a and MIP1b, are chemicals secreted by monocytes, the white blood cell scavengers. The chemokines (MIPs)dock on, or attach to, cell membrane receptors (docking sites), plugging the porthole in the cell membrane [receptor site] through which HIV enters a cell, That docking site is called the CCRF receptor. Evidence in favor of the conclusion: Moody found that “neutralization” of virus infection could be reversed by antibodies directed against the MIP1a and MIP1b, concluding that the mechanism of action of anti-lipid antibodies is that they stick to the host target cell and not the virus to prevent infection, and that a vaccine that induces such antibodies may not be able to directly neutralize HIV but may reduce virus spreading.
…

Tony Moody of Duke Univ. School of Medicine used anti-lipid monoclonal antibodies taken from patients with auto-immune disease, and confirmed that [in a test tube] the Anti-PS MABs “neutralized” virus, or decreased viral cell entry, and found that the probable mechanism was via release of cell-synthesized chemical attractant compounds called “chemokines.” Chemokines use chemical signals as attractants to other immune cells. The specific chemokines released by the antiPS MABs are called MIP1a and MIP1b, and are secreted by monocytes, the white blood cell scavengers. These chemoattractants dock on, or attach to, cell membrane receptors (docking sites), plugging the port-hole in the cell membrane [receptor site] through which HIV enters a cell, That docking site is called the CCRF5 receptor. Moody found that “neutralization” of virus infection could be reversed by antibodies directed against the MIP1a and MIP1b, concluding that the MOA of anti-lipid antibodies is that they stick to the host target cell and not the virus to prevent infection. A vaccine that induces such antibodies may not be able to directly neutralize HIV but it may reduce virus spreading

Moby, the statement, "Getting THE SAME INCREASED BENEFIT from the therapy" is a bit confusing, and perhaps the verbiage is a bit ill-chosen. I,too, wondered about the same increased benefit...as what? That aside, it could be that an immune system thought to be too compromised to respond is able to respond better when its pathway [to tumor] is unblocked by Bavi. My opinion is that the sooner they load up Bavi's spare arm with turmorcidal agents the better. Immune enhancement is only an incidental bonus.

Moby, don't remember "sketchy results" from PhaseIb in population with severely compromised immune systems, and the last set of phase II trials are/were with treatment-naive patients. Please refresh my memory on that.
Up-regulation is simply increasing the yield. We know irradiation and chemo- hasten cell death, or apoptosis, increases PS exposure on the outer membrane of cells, as does cancer. PS inversion, PS changing polarization, turning inside-out, exposing itself to the outside of a cell membrane, is normal at a stage of cellular death, during apoptosis, and the presence of PS on the vascular side of a cell wall is not an event that triggers an immune response. PS on a cell's surface lulls the immune system into thinking cells with PS are okay, that they're going through dying a normal death. Cancers, virally infected cells, and cells that make up the inner lining of blood vessels (endothelial cells) that nourish cancers all expose PS on the outside of their cell walls. The presence of PS blocks the danger signal to the immune system that there's a bad genome reproducin' inside. Tie up the PS, and cancerous cells masquerading as normals are exposed as dangerous. Immune recognition is enhanced...if there IS an immune system remaining after the serious protein/caloric depletion caused by the disease. Next, the liver's role in all this. My favorite double entendre: Life is only as good as the liver.

thurly, yep. thanks

soulofwolf, yes SK mentioned Cotara. It will be administered as a single dose IV. He characterized results with brain cancer as "very positive." Cotara deliveres 300 times more irradiation to tumor than conventional radioactive iodine treatment. PPHM will finish the 40 patient PII brain cancer trials and then move forward.