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AMAZING!#4632 Phosphatidylserine-targeting ‘betabodies’ for the treatment of cancer Xianming Huang1, Dan Ye1, Troy Luster2, Philip E. Thorpe1. 1UT Southwestern Medical Ctr., Dallas, TX; 2Human Genome Sciences, Rockville, MD
Bavituximab is a chimeric monoclonal antibody that is being combined with chemotherapy to treat patients with lung or pancreatic cancer in randomized Phase II clinical trials. Bavituximab targets the immunosuppressive lipid, phosphatidylserine (PS), which becomes exposed on the outer membrane surface of tumor blood vessels and tumor cells in tumors responding to therapy. The antibody acts by destroying tumor vasculature and by reactivating tumor immunity. Here, we generated new PS-targeting therapeutics by fusing domains of the PS-binding plasma protein, mouse ß2-glycoprotein I (ß2GP1), to the Fc region of mouse IgG2a. Such ‘betabodies’ potentially have advantages over bavituximab. They bind directly to PS, whereas bavituximab requires a cofactor protein (ß2GP1) for binding; they can be made fully human; they are smaller in size (100KDa versus 250KDa for the bavituximab: ß2GP1 complexes); and they have slower blood clearance rates. Many different constructions of betabodies were tested, each having different orientations, domains, and glycosylation patterns. Constructs were identified that bound strongly to PS-expressing cells and plates, localized to tumor vascular endothelium in vivo, and had ß-phase blood half-lives of approximately seven days after intravenous injection into mice as compared with two days for a murine version of bavituximab. Betabodies could potentially be the next generation of PS-targeting cancer therapeutics.
PS: Reminds me of PPHM: Written comments at bottom of page are a hoot
this should make your day: Huffington Post. Good weekend topic if not previously posted? (...or even if it was...) http://www.huffingtonpost.com/2013/03/28/cancer-drug-shrinks-tumors_n_2972708.html?icid=maing-grid10%7Chtmlws-sb-bb%7Cdl22%7Csec1_lnk3%26pLid%3D291208
Is anyone else having trouble with PII front-line Bavi trial results going unreported? If not, how about us being UNupdated? The failure of that trial to "event" in a significant reportable data-set before today is simply un-/in-credible. NOT eventing to date is a reportable event IMO. Someone needs to level with us about where we are in that trial. We paid for it. No report at this point appears too telling. We have seen signals aplenty of possible "downside disappointing" results, and only management's silence to [apparently] assure us that PII NSCLC results are too close to call to date. If there have been no leaks of results to date I would be surprised, and the stock price does not support optimism. I am not down on Bavi in any way. The only "take" on this post is I think it is high time to come up with results to date.
PS Can't imagine why Bavi is not being used in clinical trials with irradiation therapy by this time. The best possible spin I can apply to all this is that perhaps a subset of terminal patients are seeing a "downstaging of their cancers, and are, in fact, in the process further treatment (irradiation, gamma knife, etc) which Bavi has helped make possible. If this is the case it is time to divulge. Anything.
pharmboy, letter-perfect. I agree emphatically. Thanks
interesting, bipharm, thank you. eom
duke's boy's back! PPHM will start movin' now. Bavi- fever and excitement in PPHM executive halls is palpable even from this distance. Just hope all this doesn't go to their heads. Weekly wrap-up: money-interests continue to jockey for position, while rag-tag masses (retail) hope they're on the right side of the street to catch BigDawg's loose change. That's me. I'm there. Long and not so strong. Cheers for a glorious weekend all!
hey cj, REALLY appreciate the transcript. I didn't even know the cc. was going to happen. cheers!
eyebuy...nice post. Good "between the lines read". eom
another keeper from CJ. thanks for your time and effort. eom
geo, agreed. subset analysis of pancreatic ca trial should be a real earthshaker...good enough to get it into ASCO probably. Also, Herceptin neg. breast cancer. I like the rubric, "Bavi is the cornerstone of a great new therapeutic platform". Can hardly wait for "Bavi-E (anti-phosphatidylethanolamine)" on the other corner (joke).
King, on BAVI IMAGING: What is a "-PS index"? Any company wanting to develop a new anti-cancer drug may, in the future, be able to see on a screen in real time how effective their candidate drug is at attacking the cancer by monitoring how much -PS is created in and around the cancer. How? PS is expressed in dead and dying cells and in cancer cells. Labeled Bavi injected (or oral) collects at the cancer site where increased PS is being produced if the anticancer agent is effective in killing cancer cells. Something like the "PS index" will be established to determine the cancer lethality of a drug. This ability to see in real-time the action of anti-cancer drugs could potentially obviate the need for cancer drug clinical trials as we know them, and save a huge amount of money for drug development. Pretty amazing that Bavi may be used to monitor drug anti-cancer effectiveness even if, worst case scenario, it turns out to not be highly useful as an anit-cancer agent...etc.etc.
Eastcoastguy, lots of wisdom there, thanks. About the, "be patient and enjoy it," I don't know. I'll repeat a question posed here a couple times. Do you think the docs in New England hospitals like BethIsrael, the MassGeneral, SloaneKettering, and a dozen others, with their brains all enmeshed in PPHM technology, approve of what Bavi is going through? PPHM exec.s? Thorpe the inventor? Would the general public (educated and uneducated)in any way condone what happens in the marketplace to promising new drugs? "Be patient and enjoy it" doesn't quite get it for me.
eb0783 you are welcome to stay out of "any long drawn out speculation" about chimeric vs. humanized Bavi, but the fact that Thorpe said humanized is not necessarily better relates only to the intended application of the technology. There is no long drawn out speculation about which form of Bavi is better at exciting a body's immune response. That's a given. Thorpe gave us that. Now the question is, which form of Bavi is better at flying in under the radar (body immune response) to deliver a payload...and why would Genentec be looking at fully humanized Bavi otherwise. Two different applications. The point is that chimeric Bavi is an infantile form of the anti-PS agent which will be used a decade from now. That meaning the anti-PS platform is worth an incredible amount more $$$ than naked, chimeric Bavi battling against end-stage lung and pancreatic cancer.
volgoat and cloaked: of paramount import for PPHM stockholders and prospectives is to remember the present iteration [sic {rrdog}]of Bavi is the result of one investigational detour along the pathway of exploring Bavi-(anti-phospholipid) technology. the "holy grail" is undoubtedly an oralMAB which can be taken daily similar to oral insulin. But walk we must before running. Today's Bavi is but the "crawling" infant form trying to force its way onto a very impacted treatment table. I am certain that immunogenicity is important here. No question. But the term "immunogenicity" is usually used when looking for a body's ["allergic"]reaction to a drug. We think we know that Bavi- chimeric form is relatively free of side effects, but do we have a clue about how many times current-Bavi can be given before host vs. Bavi reaction sets in? I am sure the company knows the answer to that one. Humanized Bavi being used for cancer imaging doesn't appear to lose specificity for docking to cancer-PS docking sites and lose docking affinity "by many orders of magnitude" as suggested by your bro, volgoat. I am really interested in reading the research on this. I do remember seing in the literature that chimeric Bavi loses docking-site affinity when it it is carrying a payload. Bottom line. This technology is HUGE, and the advantage conferred on PPHM by virtue of its vast experience using the technology in humans is enormous. WE have paid for that human research (and lower animal experiments too), and to conclude that results on advanced lung and cancer patients render Bavi (Bavi technology) worthy only of the trash heap is not reasonable.
Volgoat, thanks for the information. If possible, I am interested in reading the source for "However it has been shown in several studies that humanised antibodies bind antigen much more weakly than the parent murine monoclonal antibody, with reported decreases in affinity of up to several hundredfold [which I do not doubt]", and also for, "Fully human Mab's will only reduce irritation at the dosing site, it is not any more effective, it is actually less effective for mab's". There are several aspects to consider re. this question. In general, I think most investigators would validate/agree with the following: "Fully human antibodies derived from transgenic mice are the current apex of therapeutic antibody development". [MAbs. 2010 May-Jun; 2(3): 256–265.
The immunogenicity of humanized and fully human antibodies
Residual immunogenicity resides in the CDR regions
Fiona A Harding, Marcia M Stickler, Jennifer Razo, and Robert B DuBridge]
Iwfal, I missed some of this thread, so pardon the intrusion if it is off the mark. The number of disappointing results does not necessarily predict future results, and the spin-offs alone from being the development and production arm (PPHM) of a promising new technology is huge. Remember, Bavituximab began life as mouse-man chimera, a double-armed rocket, one arm capable of effecting docking with "flipped"membrane aminophospholipids, and the other capable of bearing a payload. The inventor (Thorpe) learned that unarmed, or naked Bavi had stronger attraction to cancer areas, and without a payload, alone, induced enhanced immune response by "turning on" macrophages (garbage collectors) that discourage cell division (ie. mitosis+cancer), and imprint a long-term body immune response to the tumor. Bavituximab is not going to reverse advanced solid tumors. It attacks them. Lights them up like a Christmas tree. But large solid tumors will still require combined therapy, surgery, chemo-, and irradiation. But that is the glory of Bavi. It does not compete at the table. It ENHANCES the response to traditional therapy. HOw much? How soon? Is the "marginal good" worth the price? If not, we have fully human Bavi awaiting a mission.
...any plausible reason why PPHM should not partner will be employed for deferring inevitable approval of Bavituximab. Tell me guys, would Mr and Mrs America approve of what's going on here?! Notice that even Roche must pay its dues and also ante up in this big stakes game...
bioBS, succinct and accurate. thanks
think of the psychological difference today between PPHM as a privately held company moving slowly and surely toward the target, and a corporation with public-traded stock which is being manipulated like a puppet. And think of the difference in our mood between today, and the day after the same results were announced in September when the share price skyrocketed. After the stock price was beaten up yesterday on good news are we more likely or less likely to accept a relatively low partnership or buyout offer and be happy about getting out with some of our investment? There are some very sophisticated entities involved here.
Published Bavituximab results quite impressive overall. For those deeply involved in the treatment of aggressive cancers which have metastasized and failed primary treatment, the results of 2nd line treatment with Bavituximab are actually quite good, and point to the future use of Bavi before the cancer and its treatment reach such an advanced stage The chances of these favorable results occurring by chance are roughly the same as getting hit by a live round in a game of Russian roulette. Because of the impressive safety profile amassed over the years in lower animal and now human trial, as well as evidence of anti-tumor activity, it appears that Bavituximab will progress along the clinical trials pathway, and in the future will probably accrue several additions and modifications because of the impressive framework on which it is constructed. Over the past 10-15 years immune therapy has become a standard treatment for a variety of cancers. Monoclonal antibodies and immune adjuvants such as cytokines, interleukins, interferons, thalidomide, and BCG, and vaccines against oncogenic viruses are now well-established cancer therapies. Immune modulation is an important element of supportive care for several high-dose chemotherapy regimens, and immune activation is a central mechanism of bone marrow transplantation for blood cell malignancies. Advances in understanding of interaction between tumors and the immune system have led to new investigational treatments, and continue to drive efforts to find more potent therapies. PPHM’s Bavituximab is a novel approach to immune-based cancer treatment. Originally conceived of as a “double armed” monoclonal antibody capable of attaching to a unique docking site on cancer blood vessels with one arm, and carrying a cancercidal agent in the other, unarmed or naked “Bavi” (by itself) was also found to exhibit antitumor immune responses in the host by expanding tumor-reactive “anti-proliferative” T cells, and thereby antagonizing regulatory pathways that induce immune tolerance. Most accept that the future of cancer therapy will include immune therapy, and is likely to combine more than one of these immunomodulatory approaches to generate more effective treatments. For the time being “naked” Bavi appears to have therapeutic usefulness, and should be sped forward through regulatory channels to make it available to cancer patients. The spin-offs from anti-phospholipid related discoveries should keep PPHM at the forefront of cancer treatment for some time.
ergo, nice recap on Cotara, SOC for glioblastoma multiforme (GBM) which remains unfunded and unrecognized and languishing in the netherland between PII and PIII clinical trials. Maybe you have the answer ergo: Why, if Cotara has been approved in China for several years are there no scientific papers out of China pro or con re. Cotara efficacy for....ANYthing. Curioser and curioser IMO.
docrock,guilty as charged. I am one of the roche-genentec:PPHM connection dot drawers here, and this is, in a nutshell, my outlook. You probably noted elements of the preceding sentence to be back-as-sward. Perhaps the following is too. I think the marriage...to whomever...is one of mute/moot understanding, and I doubt if either party mentions the other by name in the boardroom for fear of future consequences. They communicate between trusted intermediaries, and agree on every move that will further delay a sudden increase in the price of poker they continue to play because of the potential/but fabled to date money to be made. As long as there is a plausible reason for the marriage to not be made public it will remain secret. When all the worst case interpretations put out by management are no longer a feasible defense of the pitiful stock price it will be allowed to rocket upward (with pent-up demand potential), and then brutally beat back down by those who control the stockprice by sheer volumes of stock in their possession. If Bavi is relly that good, face it, we don't need a partner or a marketing strategy. We'll stay. Interesting, huh.
wwtmm, you wrote,Whatever the agreement was [between a big pharma and PPHM], it happened quite a while ago.You continued, My concern is if we will be part of their[PPHM and partnering BP] future. I am confident commonstock holders will be a part of the future of PPHM. That is why I participate here. The stockholders I met at the annual PPHM meeting were most impressive, as are most posters here. There's probably a mole or two contributing, but overall, a most talented bunch...especially market, science, and legal...to assure that PPHM success will be a win:win for all involved, or to assure that nobody but cancer patients and fraud attorneys will prosper from Bavi. Someone wrote here today they're surprised Thorpe hasn't a followed-up invention to Bavi. You can't imagine whatThorpe has put out there on antiphospholipid antibody molecular/genetic engineering. He and UTSW have patents covering many[but not every] different phospholipid possible medication. Before lamenting the lack of follow-on remember those among us who would like to see new product developed on Bavi and Cotara sales funds. In new/promising discovery situations such as this the greed is almost palpable. When it comes to greed and what you can expect others to do to you, look in the mirror, then think of all the other guys out there with paramilitary surrounding them protecting front,flank, and rear. The size of this deal is attested to by the power from above pushing down on PPHM stock price lid. Holding it for as long as their financial ability allows...maybe longer. So we're talking high dollars in PPHM now. Never thought I'd see the day other countries can effect US elections and apparently even the FDA. Would the US public truly support what is going on with PPHM? Almost eight years ago I posted concern the economy would be PPHM's biggest enemy at approval time. We'll see.
wwtmm, I think you nailed it. eom
Ima, good summary. eom
chevyguy, I've followed your posts for some time, and can assure you I know even less about PPHM than you. However! I do own a 64 Chev Impala SS convertible. My first car ever. Cheers.
biopharm, here's the abstract [can't believe how needlessly abstruse it is]:
Use of 89Zr-ImmunoPET successful for imaging of drug-induced apoptosis in tumor treatment targeting phosphatidylserine
A recent issue of ‘Nuclear Medicine and Biology’ reports the positive results of a research to test the potential of ImmunoPET with 89Zr for visualizing the occurrence of apoptosis following tumor treatment with pro-apoptotic drugs. In this study [1], carried out by A. Ogasawara and her colleagues at Genentech, Inc. (USA), PGN635, a monoclonal antibody (mAb) targeting phosphatidylserine, was labeled with 89Zr and tested in animal models of human cancer, treated with pro-apoptotic therapy. The resulting probe, 89Zr-PGN635, was assessed at pre-clinical phase in four tumor xenograft models, one of which evaluated the effect of paclitaxel treatment in triggering the intrinsic apoptotic pathway, whereas the others examined the effects of treatment using an agonistic death-receptor mAb in activating the extrinsic apoptotic pathway.
The results of the study could confirm the hypothesis that the relatively long plasma half-life achieved by a residualizing radionuclide, once attached to a full-length antibody, would permit the timely visualization of apoptosis induced by the drug treatment, following specific accumulation of the probe in apoptotic tumor tissue. Indeed, high accumulation of the 89Zr-PGN635 probe could be detected in treated tumors undergoing apoptosis (30 %ID/g), as well as high tumor-to-blood ratios (up to 13 times as high). In comparison, control groups receiving vehicle or imaged with a non-binding antibody probe presented significantly lower tumor uptake.
In conclusion, it could be confirmed that radiolabeled mAbs binding to intracellular targets, transiently exposed on the cell surface during apoptosis, is a successful option for detection of tumor response to therapy. Based on this principle, new radionuclide-mAb combinations may be developed to meet the demands of specific types of cancer.
Whatcha doing? Dory asks.
researching PET-scan agents.
PET-scan? why?
PPHM licensed Genentec to study fully-human Bavi labeled with 89Zr as a contrast agent for imaging the response of all cancers to any type of chemotherapy agent. At first I wanted to research imaging competition--what agents are now being used for PET scanning, how competitive the space...cost, side-effects, specificity...and there are some good ones.
You mean Peregrine has allowed Genentec to use fully humanized Bavi for imaging in cancer patients? That means Genentec will know more than we know about fully humanized Bavi use in cancer? Maybe more than PPHM scientists know about it?
I always thought there was a Genentec-PPHM connection.
So Genentec gets to do its R&D on the cheap?
Real cheap. we're paying for it.
Dory says, reminds me of what they say about marriage. Why buy a cow when milk's so cheap?
LOL.
They ARE milking Avastin dry. that's true. There is a parallel in you parable I suppose.
They get the know-how and the inside-track on controling the stock.
Just think, they are FDA approved to use fully humanized Bavi in cancer patients. All they have to do is a couple follow-up scans.
And they also get to see any synergy.
Talk about being in the dark.
Dory says, dinner time. Ask the IH-ub board about all this. There are some pretty smart posters there.
It's Petrale sole, spinach, and rice with a mussel-stuffed artichoke as a starter.
What's the Chardonnay?
Armida, it was on sale at Oliver's. normally 19.95, but 14.95. The wine guy at the market gave it 5 thumbs up.
Talk about marketing!
dog and goat, agreed. just hope we're not goats for playing with the big dawgs. seems they're gettin' bigger and bigger, and that's not a BAD sign. pancreatic trials put things in a better perspective, actually. a cure would have been nice, and it will come, and it appears a cancer cure will be incremental rather than one cancer killer agent. that leaves a good place on the treatment table for Bavi. And speaking of one hand tied behind us in trials with advanced pancreatic cancer, seems that Bavi lung cancer trials are doing that too, what with comparing 3mg to SOC+1mg Bavi. I thought at first it was a joke. makes me wonder who's running the asylum. that is so bogus. the 3mg dose will speak for itself against historical standard of care data, and there's lots of that.
biochica, if wrote it...inferred it...fantacized...or fanaticized it, then it was written incorrectly. thanks. The point is there is no true failure here, and I certainly did not intend to write that PPHM trial planners planned failure.
Friday wrap. Apples and oranges. Compare treatment of 2 small groups of advanced pancreatic cancer patients. Tie the hands of one treament (Bavituximab) behind its back in a survival contest by assigning sicker patients to the Bavi group, and then compare median months of survival. More than 100% improvement in response rate with Bavi over standard of care (SOC), and 10% improvement in mean survival. Collosal fail(not). Stock tanks (yet again). CEO Stephen King says in advance (read my lips), "look for a huge disconnect" in the data, and then, as an aside when disclosing PII trial results, "very interesting data in a subset [of the current survivors in the Bavi treatment group]...Can't disclose more, mind you, although it is logically an overpoweringly important fact to stockholders, data probably known by stoholder biggies and other pharma insiders--potential financiers and partners for PPHM anti-PS platform for cancer treatment. Hardly a blowout with big holders increasing their investment in PPHM, and huge China-India-Russia interest. Little PPHM is going global. Hang on kids...and have a good weekend.
cloaked, good post. I went out for a round of golf and thought, "I forgot to write in my last post that the information we were not given is more important than that which we saw, and the latter was not bad, considering the wall being attacked." I have been generally very pro management in the past, but today's events smack of blind obedience to the "players" rather than to principle of stockholder interest. I believe that WHATever is known of the survivor profile TODAY is important investor information and should be divulged. This type of opacity is not good imo.
seymour, my take on today's action, like most similar announcement days with an initial pps spike, and then a tumble off the cliff, the news on that Bavi did not significantly tilt the median months of survival when it's used for advanced pancreatic cancer. As we've been reminded here ad infinitum, "median" is when half the test population dies. That does not speak to the characteristics of the surviving half of the test population. One current bone here being bounced from hound to hound today is what SK meant by a disconnect when speaking of the trials. Only a sentence or two before using the word "disconnect" he alluded to pancreatic AND lung cancer Bavi trials. A sub-plot in "disconnect" could be that the numbers today on pancreatic showed an amazing 50% increase in response rate over standard of care, but yet only about 8-10% longer mediansurvival. It seems more likely today than yesterday that Bavi has an anti-cancer mode of action, and (unsaid)probably prolongs the median 1/2 life of the remaining half, etc, possibly to "cure" in a lucky very few, depending on tumor microenvironment, stage, host immune system, where the metastases were, how large each, etc. etc. etc. Interesting, this pancreatic trial was safety-related, and I did not see any of the safety numbers, if they are out. Today's trading illustrated the increased "institutional" money interest in PPHM, with huge blocks trading on the buy side, and one large PPHM investor significantly increasing his holding. Some here think there is a large China/Russia effect in treading. The former is more conversant with PPHM's Cotara, the latter country, Russia (and India) should have a good idea about Bavi since those two countries hosted initial Bavi trials, and there are probably some survivors there. China, of course, holds the secrets of Cotara for lung cancer. My idea is to use both PPHM agents for lung cancer, and eventually I131 or tTF rigged to one of PPHM's active arms. Today some unrealistic dreams were broken, but that's the stuff of reality, huh.
cp,nice post! amen China and Russia. eom
I'm waiting to assess SK's "disconnect" between pancreatic and lung cancer data...
djohn, most would prob. consider advantage in PPHM court in trying Bavi in previously untreated patients. imo
clonepone, agreed. SK spoke of a "disconnect" between pancreatic and lung cancer data. Another potential "point of light" out there...but then, that is speculation too.
jakedog, my take is that the ECOG status is CRITICALLY important in a small trial, and the differences you point out are probably important. I am not one bit deterred by these results, and anyone who is simply does not have the experience to understand what a nightmare we are dealing with in metastatic pancreatic cancer. The reality is this: early stage disease treated with irradiation + Bavi, and/or early stage disease treated with chemo+irradiaton+ Bavi is sensible. Expecting Bavi to make a significant dent in metastatic pancreatic cancer (or lung cancer or breast cancer) is almost certainly not in the cards. Those who understand cancer will stay aboard. Those who are clueless will sell. Utilizing an exclusive "flipped" membrane phospholipid docking site still makes sense. Curing metastatic pancreatic cancer with an immunological stimulant does not.
pancreatic MOS results as expected. Unreasonable to expect the impossible in this patient mix. I believe there were interesting subset responses, as advertised, and continue to expect Bavi will be approved in the end. But as said for years, it will be a squeaker requiring continued hard work, not a slam dunk. Most important are cumulative safety results at this stage. New therapies are initiated on end-stage disease for a very good reason. Overall response rate was interesting, and probable indication of efficacy at an earlier stage of Pancreatic CA. Without arming Bavi with a warhead, Bavi as an immunological adjunct only is simply not for end-staage disease. That requires blasting powder equivalent(TNT-I131). End-stage cancer requires a Bavi armed with explosives, and this awaits proper financing which will prbably be forthcoming in the near future.