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Reminer of where this is going: "October 18, 2004 Peregrine Pharmaceuticals Announces Successful Completion of its Antibody Humanization Project with AERES Biomedical TUSTIN, Calif., October 18 /PRNewswire-FirstCall/ -- Peregrine Pharmaceuticals, Inc. (Nasdaq: PPHM) announced today that AERES Biomedical Ltd. (London, UK) had successfully completed the humanization of its 3G4 antibody that recognizes the phospholipid, phosphatidylserine. The 3G4 antibody is part of Peregrine's Anti-Phospholipid Therapy(APT) platform technology. Human or humanized monoclonal antibodies are ideal components of drugs that may be administered multiple times to individual patients because they are expected to not be recognized as foreign by the patient's immune system. "The humanized version of the 3G4 antibody is an important addition to Peregrine's VTA and APT platform technologies," said Steve King, Peregrine's president and chief executive officer. "We will begin preparing the humanized 3G4 antibody for cGMP manufacturing and evaluate the antibody for the treatment of cancer and viral diseases. The humanized antibody will also be evaluated as a carrier for therapeutic agents for vascular targeting applications."
Dr. Tarran Jones, chief executive officer of AERES, said, "We are delighted to have been able to provide Peregrine with a humanized version of its 3G4 antibody. The project was completed on schedule and the resulting antibody retained all desired binding characteristics. This collaborative project marks the 25th monoclonal antibody that we have successfully humanized using our proprietary humanization technology."
ralphazard, interesting theory.
Now that the week of Russell 3000 buying is over, what's next? Bavi liver? Why not. Mouse studies show about a 15% decreased tumor bulk when added to Sorafenib. Good. We can use that. Now really, what's next. We pretty much get it about Bavi. Time to hook up the nasties to it. Bavi can land on Boardwalk every pass, so let's put hotels on it (arm it), and get some rent money. The most amazing thing is how well the science has held up through a decade of stem cells and cloning and DNA mapping and antisense and...and...
semper, nice. Congrats. to ralphazard and you for the reminders/reviews which are extremely helpful. Wonder what dose they were using in that mouse HCC study reported in 2011. Would love to see dose escalation results. Maybe higher than 3mg? Why not. Apparently no significant side-effects. Anyone know an established "highest best" Bavi dose? LD50? (latter is a bad joke)
ralphazard, extremely timely reminder about Bavituximab potential in hepatocellular cancer. I would expect results similar to those we will find with Bavi and irradiation therapy, and with the latter I would expect dosage levels of Bavi of approximately what is being used for HCC with sorafenib (3mg/kg.)
That's a lotta Bavi.
E.coastGuy, what do we do with the info? A refund? eom
ImaSue, very informative. good post. thanks. eom
jessme,good post, thanks. I think giving Cotara to China was a good idea to let them do our research for us. Now all I want to know is, "what gives?" That China information, if available, is necessary for management to disclose. If not available, I would say China is probably in breach of contract, and cannot be trusted again (surprise!). Cotara theory, or anti-DNA-histone MAB attack on solid tumors is a great idea, even though missile Cotara is pretty large and clunky. Cotara is more rationale by about 1000 times for treating advanced lung cancer than is Bavituximab, imo. And the two could definitely be used together/in tandem in that disease. So where are the numbers? Incredible.
vol, I seldom LOL, but I did on this one of yours, "We should all email the FDA everyday asking why the control arms in Peregrine's trials continue to set new records?"
zare, do you think it a good or a bad thing that 16million PPHM shares changed hands at/near Russell "adjustment" rather than the more commonplace 2 million shares?
Zare2, good sleuthing. Keep up the fab work. That "Russell 3K krowd" is a savvy bunch, with a new twist every year. Its so much fun to be whipsawed back and forth across the "Russell Red Line" as is the lot of humble startup biotech securities.
Hey bio, great post. eom
Dew,Doubt PPHM China Operation was/is a scam. No more of a scam than licensing Cotara rights to China about ten years ago where it was/is "FDA" approved for lung cancer. We've heard absolutely nothing about Cotara in China. Do you find that peculiar? Couldn't we expect negative or positive results in their studies or clinical results. "Scam" does not seem quite descriptive of those "operations".
Paul, agree. But PPHM comes up with enough cash from wherever to move the ball forward whenever, and at an astonishingly economic savings for BP, whomever/whichever. Retail PPHM stockholders suck it in again...and again,in concert with stock dilution by the company, but the science is undeniably moving forward as Avastin clutches at exit doorframes. Genentech has publicly announced collaboration with PPHM. The two companies are working together now,considerably, on the anti-phospholipid platform, but DNA is just not "helping out" with frills right now. leaving us (PPHM) owners today with only enough income to barely pay the rent, but watch out for tomorrow. We stockholders might get smart.
geo, the $64million dollar question. It appears there is nothing to be gained by pursuing the 1st line study if the control group is a statistical outlier, a finding which puts us in the same statistical category as the flawed 2nd line NSCLC trial which (miraculously) the FDA gave us the nod on. Obviously nobody involved could withstand the fallout of another weird control group outcome. My guess is they are seeing increased months of survival in both groups, and have connected the dots. Increased months of survival for terminally ill patients. That translates to clearing the boards and bearing down on the pathway that has been opened to us. The trial results/numbers for 2nd line were quite compelling, and would probably have resulted in fast-track if not for the coding errors. Thank God for PPHM wholly owned subsidiary, MAB producing Avid. A facility that allows PPHM to crank out top quality product and obtain it on very favorable terms. For those ready to pull the trigger I would caution that the PIII go-ahead is not hamburger. Its not an accidental observation. From the genetic engineering lab to the rat lab to the human lab the safety and efficacy have held true. If it's not an H-bomb against far-advanced cancer, it has proven to be noticeably subversive.
Ethics:interesting divergence between the business/stockmarket folks and the science-few here, and interesting how delivering product to consumer is supervised by entrepreneurial scientists, medical doctors.
At this point PPHM does not suffer any negative connotations in the medical community. PPHM has, in the years I have been a stockholder, not stepped over (or even close to) the line of being deceptive/unethical in their reports to the scientific community.
That's how everyone gets comfortable with each other in the broad pipeline of investigative clinical studies. Studies on advanced disease, such as advanced lung cancer, are done to give a realistic estimate of safety. Any efficacy is a bonus. If an agent shows ANY effect on advanced disease, it might well have a profound effect on early disease. And now we know Bavi can probably be used safely in earlier disease. Can the scientific community get behind a Bavi- based therapeutic platform? I think so. The stability of the platform is hinged on safety and sensibility. It appears we might be okay on both. Bavi-based product continues to make sense...even after being starved and parched in the clinic outback for years (AKA India, Russia, China trials). IMO we know pretty much what "naked Bavi" can do. It makes sense to use it early and often. Next clinical trials should be during and after irradiation. Armed Bavi. Imaging Bavi. Bavi with chronic disease. Use it for smaller, earlier, and less lethal disease. The fact that most informed observers are still aboard speaks for their continued willingness to let Bavi show its stuff.
goodJohn, thanks for your efforts in the labyrinthine world of immunology. You wrote, "Immunocore has created a world-leading platform of bi-specific biological drugs, called ImmTACs, which exploit the power of T Cell Receptors (TCRs) to recognise intracellular changes that occur during cancer or viral infection. THIS UNIQUE RCOGNITION ABILITY of TCRs sets them apart from traditional antibody-based therapies that can only recognise changes on the surface of cells, and provides, for the first time, the ability to develop extremely potent targeted therapies for cancers that are currently poorly served. A particular feature is that the ImmTACs can be directed to target and destroy only the cancerous cells, avoiding damage to healthy cells.
It should be said that BAVITUXIMAB is also capable of recognizing changes on the surface of cancer/viral cells which reflect changes inside a cell infected with cancer/virus. Membrane phosphatidylserine (PS) flips inside out, presenting a surface antigen to target, an antigen which was previously intracellular.
here's the point: does a rational patient or physician consider a "Bavituximab" product on the basis of safety? No contest. Does a rational patient and oncologist consider using MAB Bavituximab targeted on an exclusive cancer cell docking site which is loaded with a cytotoxic agent du jeur sprinkled with a quantum of naked Bavi? It makes a great deal of sense to me.
so now PPHM has longer survivals than SOC in 1st line, 2nd line lung ca, and glioblastoma multiforme (with Cotara)? And selling for one dollar and change...hmmm.
good posts this a.m. docroc,senrex,vol,et.al. Most important, we have Bavi in PIII. That's huge. We need to stay focused on that. Does anyone know if the front-line trial was run by the same co. that screwed up second-line? There are those here who understand the basic science of anti-phospholipid therapy; there are those here who have witnessed the awesome lower animal trials. There are also those here who have seen the difficulties of transferring those observations safely and with efficacy to humans. Safety is paramount, and it looks like we have that. With well established large cancers we cannot send in a missile to cruise the area and recruit immune-fighter into the area. For large tumors we also need a missile with carrying capabilities, of being heavily armed. PPHM has that too. This has all the makings of a $4-5 sell-out for a $50-100 downstream blockbuster. Things are looking better for a BP with deep pockets than for retail stockholders. I'm still in.
PERSPECTIVE: It was never in the cards for "naked Bavi" to have a significant effect on far-advanced lung cancer. Review: Stage IIIB non-small cell lung cancer has spread to lymph nodes above the collarbone or on the opposite side of the chest as the primary tumor. The cancer may have spread to (a) the main bronchus; (b) lung lining, chest wall lining, or chest wall; (c) diaphragm; (d) heart or the membrane around it; (e) major blood vessels that lead to or from the heart; (f) trachea; (g) esophagus; (h) sternum; and/or (i) carina; and/or (j) there may be one or more separate tumors in any of the lobes of the lung. Part or all of the lung may have collapsed or become inflamed and cancer may have spread to the backbone and/or the nerves that control the diaphragm and larynx (not shown). Stage IV non-small cell lung cancer. The cancer has spread to the other lung, and/or to lymph nodes, fluid around the lungs or heart, and/or other places in the body, such as the brain, liver, adrenal glands, kidneys, or bones. Come on folks. Maybe you have to actually do surgery on large cancers: feel them; cut into them; look at surrounding tissue and blood supply. An injection of a "naked" MAB for such? This is not a setback. More an awakening from a pleasant dream? What about safety? Not even mentioned, but at this point it is assumed that Bavi- is safe. We know it can pack a payload. What about chronic disease states other than cancers?
Alzheimers and rheumatologic (immunologic) diseases? PS technology is here to stay and will require huge infusions of cash. The frontline NSCLC results do not confer a huge premium, but the safety profile is auspicious Don't count PPHM out yet.
FTM, great stuff. IL combo the way to go? eom
PPHM Bavituximab is a chimeric monoclonal antibodies which binds to a PPHM exclusive site on malignant/oxidatively stressed cell surfaces. The private landing site that beckons Bavituximab and its lethal passengers is a "flipped" membrane lipoprotein, phosphatidylserine (-PS), and the downstream effects of occupying that particular -PS cellular binding sites is that the mere act of binding the landing sites invokes the correct body response to the presence of a "worm" within the membrane perimeter. In short, Bavituximab calls in the "anti-growth" crowd for a cycle of, uh, cleansing of undesirable degenerates. Bavituximab has, in both lower animal and advanced FDA patient-trials, slowed, stopped, reversed, and apparently immunized subsets of patients against recurrence of certain solid tumors (and probably hematogenous malignancies also). Bavituximab's capability of carrying imaging agents and cytotoxic agents directly to tumor has been clearly established. The role of Bavituximab in such systemic disease as Altzheimer's and autoimmunity, and antiPS syndrome is being studied and the anti-phospholipid therapeutic program is slowly struggling toward the marketplace. Meanwhile, Big Pharma has once again revealed the extent to which we are captive to hedge fund, arbitrage, swaps, futures, shorts and other marketing frauds. And PPHM is set back a full year by an obvious outside error or fraud. Too bad those involved did not apply themselves to pure science. Wall street denizens are clearly evolving and prospering more rapidly than, say bench scientists, or medical practitioners. Cheers for the weekend, all. We'll see how long the genius of our founder, Dr. Philip Thorpe, holds out against patent jumpers and laboratory technology pirates.
biopharm, good find. pregnant with possibilities...eom
the thing that bugs me the most about biotech: Cotara, for example. IMO a perfectly logical approach to solid tumors.
Attack at the center; THEN attack at the periphery too (with Bavi). Who out there knows why the technology isn't being pursued? Somebody does. Why don't we? Surely the results are whispered about. Why aren't failed results of major corporate projects made public? Why no word(at all!) out of China in
the past decade of results there with Cotara and lung cancer? Someone knows those results. Clearly there are transparency stockholder/corporate disclosure issues not covered by the FTC. What did "they" know and when did they know it? And why can't we know it at some reasonable/similar juncture?
cheynew, that's exactly why the price is what it is..for the past ten years.
Bavi will be approved because it is such a stable and safe launch platform; a stable MAB rocket that homes in on cancer endothelial cells; and that docking site is a PPHM exclusive...
what role do any of you think the BOtrustees at UTSW plays in partnership/buy-out/go it alone discussions? Hands off? Active involvement?
my observation is there are fewer and fewer MD-BP kickbacks and perks with each passing year, and almost certainly fewer than in any other business I can think of. The reality is that private practitioners are/remain businessmen/entrepreneurs, and must meet the payroll and bring some personal income to the bottom line. Most don't even talk with pharma reps in the office anymore. Docs are human, but overall they have more influences encouraging ethical behavior than discouraging it. I can speak with some authority on this after having been an active consultant for years with the enforcement division of the California Medical Board, sitting across the table from errant physicians.
almost funny: emblematic of what is being written about BP control of ASCO is the newspaper clipping my wife just handed me, "Cancer drugs boost Merck, Bristol shares", mentioning PD-1 drugs, or the promise of immunotherapy for advanced melanoma. I was involved in cancer immunotherapy in the early 70's, when BCG was being studied for use in melanoma, and here we are 40 years later. There were newspaper articles then similar to the one today. Cancer immunotherapy is simply not going to make chunk-size (>1cm) tumors disappear. Immunotherapy is a reasonable adjunctive treatment, and at least one should/will probably be thrown into the chemo/irradiation/surgery treatment mix. Will it be Bavi-?
It is sensible to me.
KT,I like your post on PPHM going it alone. For years I have said that is a viable option if/when product is clearly better than competition, or fulfills an obvious need. No "sales" force is necessary. You were mostly right about doctors being in the driver's seat, but some huge caveats apply. Number one concern is family and self. We all want to keep our license to "practice" another day...to feed/clothe ourselves, etc., and therefore avoid being out in front of the crowd. We are bound by a legal concept, the "standard of care" which is a bit fuzzy, but the implication is clear. Can I prove that a prudent professional would administer this treatment choice vs. another more time-tested one? Oncologists are in the hotseat for malpractice suits, almost as much as radiologists and obstetricians, because a relatively higher percentage of their patients die, and they are dealing with remote and often greedy family members, and not the patient they have established a relationship with. So in the rare instance the patient is daring and the doctor is willing, what about the bereft family. Using standard of care, whether effective or not, is often preferable to trying a new approach with more promise.
Are to believe there was a retail crowd at the door this morning, and all of retail has gone away the whole afternoon? I would say PPHM news still has a pretty firm lid on it, as well as the share price. Unbelievable, this.
where are MarthaStewart/SamWacksoul when we need them...
2ndstr: you're reading it right. That's an excellent summary of Bavituximab mechanism of action.
jbainseky, CLDX flagship rindopepimutis an anti-EGF, (ectodermal growth factor inhibitor). EGF is a docking site on many solid tumors which was initially explored by ImCL with ERbitux, and then by others. CLDX rindopepimut might or might not prove successful, but one point to contemplate is that it is one of many anti-EGF approaches, and the anti-tumor anti-EGF pathway is full of mutation bypasses which can thwart that approach. Bavi- is the first generation of anti-PS antibodies, and one of its virtues is that it homes in on a surface docking site on vascular endothelial cells and not on tumor surface antigens, per se. Endothelial cells, which not cancer cells, are remarkably stable genetically, and do not mutate away from the therapeutic value of the MAB. At first glance ClDX has some interesting tickets, but I'm not sure I would say they are at a comparable level of development, and certainly do not have the vast potential Bavi- has to treat almost all solid cancers.
vinman2, sorry. Took a sunset walk on Pebble Beach golf ourse, and had a pizza at Il Fornaio in the Pine Inn in Carmel.
entdoc,
I said, "fully humanized Bavi which is now "in production" is said to does have the diminished affinity to the -PS binding siet that the conjugated chimeric form does issue for reasons more technical than the intent of this post. }}
You said, "That sounds like an excuse provided[by] someone who doesn't know what they are talking about. So, why hasn't PPHM announced that the fully humanized Bavi will be made and used as an antibody drug conjugate?"
I think they have been looking at that, vinman, and I also think PPHM has said so. But, then again, I could be confused about that."
What's your overview of the PPHM -antiphospholipid antibody platform?
I said, "{{Something happened during lower animal trial: Bavituximab without a payload, "naked" Bavi- was noted to be immunogenic, stimulating the body's immune system. With that discovery PPHM scientists moved that direction, toward immunological attack. In my mind that was an error, Immunocancer warfare is a splendid and idealistic avenue of inquiry. Immunotherapy WORKS. But it isn't the atom bomb against that calibre opponent. Rhetorically I asked, "What happened to loaded Bavi?" I can't recall any information from PPHM about what happened to that program? Pfizer at UCSF (northern California) has announced revisiting that strategy...and for a very good reason. We need the bomb. I said, "Rumor has it that when one arm of Bavi is loaded with a small molecule, the other "available" arm cannot bind so readily or solidly to target. }}
You said, "Drug conjugates for MAbs can be linked to various portions of the Ab. In fact, multiple conjugates can be added to a single MAb to make it an extremely potent delivery vehicle. If PPHM tried to arm Bavi on one of the variable arms, saw it lose specificity or avidity then stopped rather than try and move the conjugate to other parts of the Ab, like the Fc portion, then they are imbeciles."
THIS IS IMPORTANT.
We know -PS investigators are not imbeciles (come on!), so we can assume the variables have been shepherded into labby notebooks. PPHM apparently has the warship that can take it to cancer. Let's keep moving that direction. Now what? . That knowledge is out there, and a number of people have it. I don't. I'm a clinician.
vinman2, one-thousand welcomes... a northern california DNA scientist. your handle even makes sense. About your assertion I may be confused? Everone reading here knows that.
I said, "{{Bavi- was developed as a double-armed MAB vehicle to carry cytotoxins to a specific docking site on vascular endothelial cells, the inner lining cells of blood vessels which nourish cancers and allow them to grow. Bavituximab was originally an anti-angiogenesis MAB in the same category as Avastin, but with a different, exclusive docking site on membrane surface -PS. The idea was to target tumor vasculature. }}
You said, "Unless specifically engineered, all IgG monoclonal Abs have two arms which comprise the variable portion of the antibody. I'm with you so far...continued
carboat, ASCO docs, like everyone else, are looking for hammers and not velvet gloves. The anti-PS platform continues to look very promising, and has a solid base in Bavituximab. What more needs to be said at ASCO. The information is there. It is not a cure. Bavi- was developed as a double-armed MAB vehicle to carry cytotoxins to a specific docking site on vascular endothelial cells, the inner lining cells of blood vessels which nourish cancers and allow them to grow. Bavituximab was originally an anti-angiogenesis MAB in the same category as Avastin, but with a different, exclusive docking site on membrane surface -PS. The idea was to target tumor vasculature. Something happened during development: Bavituximab without a payload was immunogenic, stimulating the body's immune system. What happened to loaded Bavi? Rumor has it that when one arm of Bavi is loaded with a small molecule, the other "available" arm cannot bind so readily or solidly to target. Again, this is my "understanding" only, but it is said that fully humanized Bavi, now "in production" does not have that issue for reasons more technical than the intent of this post. Therefore, for reasons of terrible financial squeeze, PPHM was forced to go with unarmed "naked" Bavi, and say to ASCO, "Isn't this interesting what an unarmed MAB can do when it plugs cell surface-PS receptors. AMAZING. Bavituximab is one of the many examples now extant of how using tumor immunology might prolong life.
biopharm, VERY good question. Answer is "yes". The idea of double-fisted, double-armed Bavituximab evolved in Thorpe's labs as a MAB capable of carrying a small molecule cytotoxin to a specific docking site on cancer. Truncated tissue factor tTF is one such small molecule that wreaks havoc on the clotting system, and has been studied in Thorpe's lab as well. That is the reason why they want someone who is expert at conjugating (arming) MABs with small molecules.