jess, I think Haynes and PPHM had an agreement to wait for until after this last patent was approved. Maybe even the same reason re. all results of hepatitis trials...etc.

Wook, the secondary immunity is not due to residual Bavi, but is probably due to clonal selection within the patient/rat immune system. The exact mechanism of immune amplification is not completely understood, and the increased immune competency may or may not be measurably present, but reappears sometimes even in the distant future when the organism is challenged. It is not unusual to get an abnormally robust allergic response on second exposure to many allergens.

dia,precisely. I would use that combo- on myself in a heartbeat. But where to get it... Naturally I'm hoping to survive long enough to see the all-human models!

wook,sumpin'like that. You're right, we've known for some time that Bavi "upregulates" immune response. Don't think we knew it might help confer immunity to re-challenge (2nd set phenomenon?). However, we should remember that the phenom. was presumably only seen in 13%...the survivors. That presupposes a "subset" of test subjects [rats], or some other undetermined variable in the 13%.

wook,whatcha mean,"once the body recognizes the cancer it is programmed."?
Some cancers are weakly/minimally immunogenic...ie...they do not tilt the body's alarm system when getting established. Glioma is one. Sarcoma is another. In this case, Bavi seems to increase body's immune-police response to second exposure to tumor, and evenly weakly immunogenic tumors. Thorpe postulates that "[Bavi] induced immunity to[reimplanted] tumor cells is [via enhanced] dendritic cells that help generate specific [killer] T cells.
We know that irradiation and chemotherapy causes more PS inversion. Another conclusion Thorpe draws from this work is that since PS is seen on cancer cells naturally, and is increased during chemo- and irradiation treatment, the membrane PS is acting AGAINST body immune defenses. The PS likely suppresses tumor immunogenicity, and 2aG4 blocks this tolerogenic effect...i.e. unblocks the body's immune response.

cj,thanks.Ramifications are immense. Thorpe reported that he injected braintumorcells[glioma,rats] which grew inside the brain to form solid tumors that later infiltrated throughout the brain. Adding Bavi to standard irradiation treatment doubled survival time, and cured 13%, much better than results with either agent alone. I believe similar work was reported years ago. The amazing thing about this report is that treatment with Bavi induced IMMUNITY to re-establishment of tumors when surviving animals were re-injected with tumor cells. MOST interesting is that glios are "weakly immunogenic," that is, they do not normally alert and provoke a body's immune system to send out killer cells. The report did not state how long the protective immunity lasted.

dia76,nicepost,thanks. Agree that all must du their own doo
diligence, but everyone needs to get started somewhere, and a tip from a knowledgeable source got me started: Golfdad way back on the Imclone RB board. My understanding of basic immunology came at great expense and time, and now antigen and antibody are almost righthand-lefthand familiar, and MABs, or targeted therapy, or increasingly specific therapy, makes sense. That's why I jumped on the Cotara concept: target the necrotic center of cancers; carry a payload of a known cancer killer, Radioactive iodine. And PPHM's "ace-kicker" is Bavituximab, not necessarily revolutionary, but certainly sensibe because of its utility: calling in immune fighter cells; destabilizing the cancer's structural matrix; capable of carrying a cancercidal agent; increases sensitivity of tumors to irradiation; improves effects of chemotherapy; the MAB has exclusive docking sites (inverted PS) on cancer cells and virally infected cells; safe; progenitor of an entire "line" of anti-PS agents of which Bavi is merely the beginning. Yes, it all must make sense. The burn rate at PPHM should be covered by Avid sales, PPHM's in-house MAB manufacturer, or if not, management shouldn't be hiring all those new Avid folks. PPHM future is bright. It has arrived, albeit it relatively naked, in the big leagues.

lafont:10 years ago on another board, someone posted that the best thing about PPHM stock is how nice it fits into grandchildrens' Christmas stockings: a stocking stuffer!
You can give it away by the bushel basket (and take it back if the price goes up...that is, if the kid is still young enough).

someone watchin'? when it pops up to baseline at day's end. This is hardball, and NYC is in there pitchin'. There's only one way out though, and that's up and over. imho

a friend asked about IMMU, a biotech which has licensed out a fully humanized MAB to UCB, Brussels, www.ucb.com, a biotech that does R&D and commercial development of innovative medications with focus on CNS and immune states. IMMU,the New Jersey biotech, has a MAB in stage IIB for Lupus. IMMU stock peaked at $6 in Sept, and is about $3.80 now, two months later. Reminds me of almost where PPHM is. I should think that Merck AaG/Europe should have some Cotara news soon, if not the Chinese.

what are causes of biotech pipeline obstruction? That a few hundred $million couldn't punch through. Huge players now.

jess, pretty interesting stuff. BEZ235 is a phosphatidyl inositol-related compound, and PI is a sibling of PS, or phosphatidyl serine, the compound of concern with Bavi. As mentioned before, the whole field of membrane "phospholipids" is burgeoning, and it may be what we need most in the front office is a legal beagle guarding against patent infringement. But BEZ235 is not an MAB, and may be administered orally. It apparently primes the system for irradiation therapy by boosting the metabolism of normal cells and increasing their ability to withstand the irradiation to the detriment of cancer cells. An eye opener. UTSW (Thorpe's home) is doing the research. Thorpe was not mentioned, nor was Peregrine. UTSW doing great things. http://www.reuters.com/article/pressRelease/idUS152427+21-Jul-2009+BW20090721

jess, you taught me sumpin'. All this time I thought BMY bought out ImCL, and it was Lilly. Guess the latter outbid the former $70 to $62 per share. Before the buyout BMY owned 17% of ImCL. What a POS Lilly got.

an eye-popper,today's trading. underwhelming volume. The story hasn't gotten "out there" where retail trade lurks. Someone call Martha.

EZ I remember you from...how many years back? Sounds like you're doing it right. Best wishes

EZ,you buyin' tomorrow?

jess, yess! thanks. interesting stuff, China. Cotara!

jess, that should put it all in perspective. China has Cotara rights for People's Republic, and PPHM has an agreement with Merck KGaA for Europe. A couple good places to farm out the foot-work. KGaA thinks enough of it to list it in a patent applic. for a new "nucleic acid immunostimulant", a product they KGaA hope to use before anti-cancer drugs, like Cotara, to "prime" the immune system.
“Techniclone Corporation and Merck KGaA Sign Agreement On Use of Tumor ... I Clinical Trial in Europe With Novel Tumor Necrosis Therapy Cancer Agent” ... More on the MERCK/KGaA TNT Collab: http://tinyurl.com/yud7pw ...
siliconinvestor.advfn.com/readmsg.aspx?msgid=24700435 - Cached - SimilarImmunostimulatory nucleic acids and cancer medicament combination ...
**It is often the case that subsequent rounds of anti-cancer therapy are ...... (pancarcinoma specific Ab) Cancer Techniclone Corporation/ TNT (chimeric MAb to ... neuroblastomas Genetics Institute/AHP GNI-250 Mab Colorectal Merck KgaA ...
www.faqs.org/patents/app/20090155212 - Cached - SimilarTriple
***In still another embodiment, the cancer medicament is a hormone therapy. ...... Medarex/Merck KgaA, MDX-447 (humanized anti-EGF receptor, EGF receptor cancers ... Techniclone International/, TNT (chimeric MAb to histone antigens), Brain ...
www.freepatentsonline.com/y2006/0211639.html - Similar
by RL Bratzler - 2006 - All 4 versions

Serious allergic reactions to administered chimeric MABs now on the market [ie Erbitux] are acknowledged to be about 5%. It appears that even patients with pre-existing "mouse anti-bodies" [most of the world's population] may have an average 44 day window of treatment before incidence of reactions spikes. This is my own conclusion from skimming the data.

Next Google citation on allergy a thriller]: "Mysterious Allergy Afflicts the South by Sheila Read [filed under: health & medicine; article date: january 2008]."
The story is intriguing. Some populations in this country's South have "falling out of bed [anaphylactic shock] reactions to Erbitux. The biotech police move in to investigate, and find the patients' pre-existing anti-bodies to...mice? They have not reached that conclusion...yet. Any mouse exposure in your past?

wookie, great posts. Agreed about possible over-concern re. allergic reactions, but a concern none-the-less. This board can help all of us, doctors and patients, put the concern into proper perspective. I began researching both positions by Googling "allergic reactions to Erbitux," and found this intriguing [unreferenced?] statement:
"...Now researchers funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, have discovered that specific pre-existing antibodies cause the severe reaction to .... [Erbitux].Cetuximab,... an immune-based therapy commonly used to treat persons diagnosed with head and neck cancer, or colon cancer, marketed as the popular brand Erbitux — a product of ImClone Systems Inc. and Bristol-Myers Squibb Company. Find more details from NIAD/NIH."

Implications of China study of 2007 are huge. The entire TNT therapy pipeline is in and open. PPHM has clarified its rights. China is progressing rapidly via People's Republic Department of Defense. PPHM has worldwide rights to Cotara, and much of the technology, including recipes, cooker, and ovens. Coasting behind China's technology. Good strategy. Give the domestic rights of Cotara away to push is forward.
Excellent. PPHM front-office has its hands full...but they're also shepherding first-rate properties to market.

Anyone! What happened with Cotara report[7] ysterday? Here's a great recent article on Cotara "allergic reactions" ("immunogenicity". What's happeninig in China? Read on. Cotara with Lung Cancer in People's Republic shows "minimal" immunicity in 5 of 89 patients being treated for lung cancer. Route of administration does not appreciably change the side-effect profile. [citing authors listed below]:
Immunogenicity of Iodine 131 chimeric tumor necrosis therapy monoclonal antibody in advanced lung cancer patients
Hui Wang1, Chuanping Cao2, Beilei Li3, Shaoliang Chen3, Jun Yin1, Jing Shi1, Dan Ye2, Qun Tao2, Peisheng Hu4,
Alan Epstein4 and Dianwen Ju2
[note "epstein"]
Institute of Microbiology and Epidemiology, Academy of Military Medical Science, Beijing, 100071, China
Shanghai MediPharm Biotech Co., Ltd, 865 Zu Chong Zhi Road, Shanghai, 201203, China
(3) Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
(4) Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA
Received: 5 March 2007 Revised: 12 September 2007 Accepted: 13 September 2007 Published online: 13 October 2007
Abstract
Purpose Iodine-131 radiolabeled chimeric tumor necrosis therapy monoclonal antibody (131I-TNT) has been approved for the treatment of advanced lung cancer in China. In the present study, the immunogenicity of TNT was studied in advanced lung cancer patients using BIACORE and enzyme linked immunosorbent assay (ELISA) methods.
Experimental design Serum samples from 78 advanced lung cancer patients were analyzed for antibody development to TNT after systemic or intratumoral administration of two doses of 131I-TNT. Patients’ sera were obtained before, and 2 weeks and 2 months after 131I-TNT radioimmunotherapy.
Results Four of 78 lung cancer patients (4/78 or 5.13%) developed antibodies to TNT as measured by ELISA method, and 7 of 78 patients (8.97%) development anti-TNT antibody as measured by BIACORE biosensor after 2 doses of 131I-TNT administration (P > 0.05). All the 4 ELISA-positive patients were also BIACORE-positive. Among the 7 BIACORE-positive patients, 5 (of 42, 11.9%) patients receiving intravenous TNT injection developed antibodies to TNT, and 2 (of 36, 5.56%) patients, receiving intratumoral therapy developed antibodies to TNT. The route of administration of the radiolabeled TNT antibody was not a statistically significant factor in the incidence of anti-TNT antibody. Detailed BIACORE serological analysis showed that the induced antibodies were mostly of the IgG1 subclass.
Conclusions 131I-TNT was immunogenic in only a small minority of advanced lung cancer patients (8.97%). The route of administration did not statistically influence the incidence of anti-TNT antibody after TNT radioimmunotherapy in lung cancer patients.

jess, I'm not so sure Wikipedia is a joke. In fact, the MAB citation was pretty good. You're right that it should be taken as only one byte of information, and one should look at the cited bibliography section. Good luck to all. We're still trackin'.

what happened to Cotara info. from yesterday? did I miss it?

jake, Bavi is not "doa". The information you posted here, written by Thorpe in a grant application, is simply the first thing I've seen in writing re. "allergic reactions" to Bavi. There has never been any evidence to indicate that Bavi would be any different in that regard from other "chimeric" [part-mouse/part-human MAB constructs, like, say, Erbitux, which is on the market. All chimeric MABs share the same problem. It's a given. That's why a fully-humanized MAB is preferable, and when we have a fully-human version, we will be looking at the next best construct. That's the nature of science.
Having said that, we will only know Bavi side-effect profile after that part of the trial has been published, and it is extremely doubtful that the profile will knock Bavi out of contention for further testing and advancement. Obviously a fully-humanized Bavi MAB would receive a great welcome from those watching events at PPHM.

jessme, nice post, Thorpe's research grant application says it all: "...it was discovered in clinical trials that bavituximab is immunogenic. Repeated treatment of humans [with Bavi] induced anti- chimeric antibody responses [allergic reactions] against murine [mouse protein] components of the antibody [MAB Bavi]."
In print from the hand of the master that current Bavi- construct is not going to fly. No suprise its mouse-parts cause allergic reactions. Commonplace occurence. The best part is that the anti-PS platform is sensible, still alive, and moving forward in a logical manner. I agree that funding at this point should be no problem, and that the program will go forward.
We still have to figure out how to make money from it, and the sooner the better. I don't expect the current corporate administrators to be in place next year unles more stock price support is put in place.

EZ, didn't reallize Garnick said "PPHM needs one niche approval, and then we get movin'," but that is the point we've been talking about with Cotara and GBM, and the latter cancer is one that, although small in numbers, is capable of firing public imagination. Was I wrong re. the catheter placement? Is it via spinal tap (LP) or skull portals. Latter seems more likely. It's great getting old.

EZ, yes Cotara is a compelling story to oncologists accustomed to using systemically administered radioactive Iodine for cancers. Correct me if I am wrong, but GBM trials were thought to be, at the time, the only ClinicalTrials avenue possible because of the formidable costs of trials.
After it became apparent that the large body-size of Cotara was a problem, especially crossing the blood-brain barrier, PPHM switched to delivering Cotara to GBM brain tumors via a special catheter threaded up the subarachnoid space via a spinal tap. The strategy at the time of starting the GBM trials was that if Cotara can significantly impact GBM, then it can probably have similar or greater effect on any other solid tumors, thus opening the possibiliity of using Cotara off-label for all solid cancers. I've said this so many times it probably makes readers ill, but Cotara, especially a newer generation fully humanized Cotara, is one of the most sensible anti-cancer strategies I can imagine. Chins up crew.
This is a shake-down, and that's nuttin' like a meltdown.

jessme: sales volume speaks volumes. What more needs to be said? when the scent of money becomes stronger (ie when daily volume is over 1mil for a few weeks), that's when the action begins. I am past ready. How about you?

gandolphin, thank you for the report.

Kelly from old RB days. Are you out there? Garnick is your dream come true. Seems it is all roses from here (but it might be springtime before we can sniff them).

thanks notunco. appreciate the effort and report

no long action, no short action, no action whatsoever. That is not the WORST scenario, but clear evidence that action elsewhere is more compelling. Just put in an order for 1K at 3.28. We'll see. Good luck all.

drragmop, all the PPHM study parameters I've seen include a patietn's right to continue treatment after the sudy ends.
RightUR that follow-up in the patients will be interesting. More interesting is if that information ever surfaces.
One problem that will arise at some point in Bavi treatment is allergic reactions since Bavi is not fully humanized yet. But Bavi is apparently so well-engineered and manufactured that it has less immunogenicty scatter than, say, ERbitux or Avastin. As mentioned before, BMY made a huge mistake taking on Erbitux, but made a great buy with ABGX which has an all-human EGF agent in advanced trials. So hopefully missile-Bavi does not cause the immune disturbance Erbitux and Avastin do. I say that with fingers crossed because the side-effect numbers from pIII trials are pending. The reality is...even if Bavi side-effects are a problem, there is always the promise of a fully humanized form on the horizon.

sunstar, right on.

JGal, nice. Yes, Garnick aboard does wonders to credibility. IMO he about doubled the share value. That's what coulda happened without that well-timed announcement. Nobody said the big leagues will be easier. Stockholders must be attracted to PPHM in order to support the share price, and although PPHM continues to be a compelling story, those posting misgivings here are often right. The guys at PPHM home plate and dugout have done nicely during the past 12 troublesome months, and deserve remuneration in relation to increase in stock price during that time. Stockholders need incentive too, and one glance at PPHM stock tickers for past 10 years tells a story that management and background money -men needs to recognize: they are not the only ones at risk. Stockholders "stayed the course" waiting for better days, adding shares of stock not for greed alone, but with hope for a reasonable "next-step/next-generation" approach to treatment of cancer and viral disease. They are a noisy lot, PPHM stockholders, and will be heard. They gave management another 12 months pass because it was a tough year last, and we're a thousand times better positioned going into fall, and 2010. The theoretical underpinnings of PPHM anti-cancer/viral technology appears sound, and even though Anti-PS might not be public buzz right now, scientific literature is blossoming in citations re. PS, anti-PS, a phenom similar to that seen with other great medical steps forward.

azure, nice post, thanks

nh: Cotara and Bavi seem a sensible approach to liver cancer. I encourage continued efforts. If it is EGF receptor positive I would consider ABGX/BMY new fully humanized EGF MAB. I can help let me know, but we should probably take this to "private posting" in the future. Best wishes.

jakedog: An ENTdoc:Otolaryngology/Head and Neck Surgery. NH,as I recall, your bro. has GBM. His best shot for Cotara is where the work is being done because of their experience with the delivery catheter. If he is in Houston and wants to try Bavi, and it is available for compassionate use, he should be able to pull that one off at MDAnderson. That institution should be interested.
stoneroad: thanks for the kind words. PPHM needs Sam Waksal? He's probably available. Didn't last long at any of his other research posts. It was Sam Waksal who got me interested in the entire field of monoclonal antibodies, and who also made me some money on a product that pales in comparison to Bavi. Doubt if Martha Stewart is ready for more biotech though.
I also jumped on the PPHM train too early, but someone has to do it! Now we just have to be sure we don't lighten up at the wrong time.
The volume is still light enough to be easily manipulated by a single entity so I don't take this market action seriously.