TCLN - a very good research summary from: sherwoodcoastsgroup.com
A long read but worth it, IMO.
Hopeful researchers predict a treatment explosion!
TCLN HAS 6 BIG TECHNOLOGIES!
TNT (Cotara) = TUMOR NECROSIS THERAPY ? Monoclonal antibody that can target ALL solid tumor cancers. Attach whatever you want to TNT, and it will carry it with pinpoint accuracy to the tumor site.
VTA = VASCULAR TARGETING AGENTS ? -Technology that can target ALL solid tumor cancers. Used to carry blood-clotting agents precisely to the tumor. These clotting agents cause tumor only blood clots, thus choking off their blood supply resulting in tumor death.
VEA = VASOPERMEATION ENHANCEMENT AGENTS -- Monoclonal antibody that carries compounds that cause the blood supply of the tumor to increase, thus allowing more chemotherapy drugs to enter the tumor and kill it.
2C3 = ANTI-ANGIOGENESIS AGENT ? Monoclonal antibody that blocks VEGF receptors on tumor vessels, thus halting tumor growth.
LYM-1 = Monoclonal antibody used in the treatment of intermediate and high-grade Non-Hodgkin?s B-cell lymphoma.
MAT = Technology that allows ALL monoclonal antibodies to work better.
4 TECHNOLOGIES TO TREAT ALL CANCERS!
TUMOR NECROSIS THERAPY can target ALL solid tumor cancers. TNT can deliver any toxic agent precisely to the tumor site thereby limiting toxicity. Whatever is the best tumor-killing agent, TNT may improve it.
VASCULAR TARGETING AGENTS can target ALL solid tumor cancers. VTAs cause blood clots within tumor masses choking off their blood supply causing tumor death.
VASOPERMEATION ENHANCEMENT AGENTS can target ALL solid tumor cancers. VEAs may increase the effectiveness and reduce the toxicity of all chemotherapy drugs.
2C3 ANIT-ANGIOGENESIS AGENT that stops the growth of tumor blood vessels, stopping the tumor in its tracks.
Four potential blockbusters, all owned by one company. (TCLN)
TCLN INVENTED COLLATERAL TARGETING!
TCLN invented the collateral targeting field. Instead of looking for antibody binding sites on the surface of cancer cells like most other monoclonal antibody technologies (the needle in the haystack approach), TNT, VTAs and VEAs all utilize collateral tumor targeting. Collateral targeting is the utilization of antibody targets other than cancer specific cell surface antigens. Therefore, it is not necessary to develop a different antibody for each cancer type to be treated.
TNT IS NOT ONE DRUG ITS MANY!
TCLN?s platform technologies. You have probably heard the term ?platform technologies? used when describing some of TCLN?s technologies. Following is an explanation of this term.
TNT (Cotara). Although TNT is currently in clinical trials for the treatment of brain cancer, pancreatic, prostate and liver cancers, it has many other uses, thus coining the term ?platform technology?. It is in fact a platform on which to build other cancer therapies and diagnostic agents. WHICHEVER APPROACH TO TREATING CANCER IS THE BEST, TNT MAY BE ABLE TO IMPROVE IT.
The TNT monoclonal antibody is simply a carrier for various compounds that actually cause the desired effect on the tumor. The TNT antibody alone (naked) has no tumor killing capabilities. The easiest analogy for this would be to think of TNT as a Cruise Missile. A Cruise Missile alone has no use as a weapon of war. When you attach a 2000 lb. bomb to it, it becomes a very deadly weapon with precise targeting capability. Attach a biological weapon to it, and it becomes a weapon of mass destruction. Attach a nuclear warhead to it, and, well?.. you get the point. The Cruise Missile and TNT are both precise targeting vehicles. TNT is just a biological targeting vehicle. In the current clinical trials TNT is being used to deliver radioactive isotopes to the tumor (for reasons explained in previous posts). It should be comforting to know, as investors, that if this approach is not effective, there are many other uses of TNT. This reduces the risk we are bearing and tremendously increases the up side of the investment. If the current treatment is successful, we could have a major blockbuster. If some of the other uses of TNT work, we could have an unbelievable blockbuster.
TNT HAS MANY USES!
TNT is also a tumor imaging agent. There are several tumor imaging agents and devices on the market. All are cancer specific and at most can image several cancer types (breast, colon, etc.). TNT could be the first universal cancer imaging agent. There are several methods of creating an image. Radioisotopes are a standard for imaging (using a different isotope than Iodine-131). Phosphorescent dyes are another approach to cancer imaging. What ever the approach may be, TNT could be the delivery mechanism for the imaging agent. Since early detection is the single biggest factor in determining the outcome of cancer treatment, a universal imaging agent could be invaluable in the war against cancer. Such a cancer detection agent could become a standard screen for sick patients that may be suspected of having cancer. Patients in high-risk groups could be screened routinely. A universal cancer imaging and detection agent may have a larger market than cancer treatment. After all, you will certainly be imaging all patients with cancer and probably many more patients that come up negative. You could build a company around this product alone.
TNT can deliver chemotherapy drugs. One of the problems with chemotherapy is that the drugs are very toxic. Since chemo drugs are not selectively targeted, they poison the whole body indiscriminately. In essence, chemo poisons your whole body, hoping your tumor dies (cancers cells are weaker than healthy cells) before you do. This is why there are so many side effects with chemo. With TNT delivery of chemo drugs you could localize the extreme toxicity at the tumor site only. By injecting low doses of TNT/chemo, the patient would be exposed to lower amounts of drug while TNT would accumulate in high volumes at the tumor site. This would reduce the side effects of chemo, leaving patients healthier to withstand more aggressive dosing regimens, hopefully resulting in greater efficacy. A good analogy for this would be to dump a small amount of metal shavings in water that is being circulated through a closed loop piping system. Somewhere in the system place a magnet. Over time most of the metal shavings will accumulate at the magnet. Therefore, the water has very low amounts of metal shavings while the magnet will have a large accumulation.
TNT can deliver radiosensitizers to tumors. Radiosensitizers are drugs that cause radiation therapy to be more effective (5-FU, fluorodeoxyuridine, thymidine analogs, etc.). Radiosensitizers would be effective for increasing the efficacy of external beam radiation and TNT/131-I.
TNT can deliver Pro-Drugs. Pro-drugs are drugs that are not toxic until they come in contact with the tumor or they are targeted to the tumor and later a triggering agent is injected causing the drug to become very toxic selectively at the tumor site. TNT would be the perfect targeting agent for pro-drugs.
TNT can deliver liposomes. Liposomes are fatty structures that are used to encase toxic drugs so they are not toxic to the whole body. Liposomes are made to dissolve at the tumor site (at different ph?s) releasing their toxic payload (Trojan horse concept). Although they reduce toxicity of most chemo drugs, they have limited efficacy because of the inability to selectively target the tumors and accumulate in high volumes. TNT should be able to increase their accumulation at the tumor site.
TNT can deliver DNA and antisense to tumors. In many cases these compounds will need to be delivered to the tumor site for their mechanisms of actions to work properly. TNT can do this to.
TNT WORKINGS This slide of Cotara "lighting up" a brain tumor says it all!
techniclone.com
If you go to the following site you are going to see a CAT scan of a brain cancer patient's skull. The images are layered like slices of an orange.
Click here
The white in the image behind the nasal cavity shows where the tumor is. As you can see, the tumor has 2 main masses connected by cancerous tendrils.
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Now we know where the tumor is. The next slide is a radiograph image (measures the gamma rays being emitted by Iodine-131) of the same patient after Cotara was administered.
Click here.
As you can see, the radioactivity appears to be localized in large volumes at the tumor site. The radiation will sterilize the surrounding area and kill any living cancer cells.
Cotara is specific to tumors (necrosis) and did not show significant migration from the tumor site. This non-migration limits the side effects of the treatment.
TNT SEEKS AND DESTROYS TUMORS!
Slide 5 shows the specific necrosis targeting ability of Cotara.
Click here
Slide A shows a tumor mass section sliced in half. This section is then stained with a substance that binds to living cells. These cells show up as the dark areas of the slide. The lighter areas are necrotic tumor tissues.
Slide B shows the same tumor mass section. This section was exposed to TNT with a radioactive isotope attached (while still in the mouse). A radiograph showing where the radioactivity is located images this section. The black areas show the radioactivity.
As you can see, they are negative images of each other. This shows that TNT binds to necrotic tissue and not healthy tissue.
TNT EFFICACY
Click here.
TNT ? ONE ANTIBODY, MANY TUMORS!
Cotara (TNT) appears to be able to target tumors or necrotic tissue just as Dr. Epstein intended it to. The beautiful thing about it is, contrary to most other technologies being developed, it can target many, if not all, solid tumor cancers.
Click here.
VASCULAR TARGETING AGENTS
In the simplest terms, the Vascular Targeting Agent technology capitalizes on the fact that tumors have a poor blood supply. The VTA technology in effect attempts to make the poor blood supply issue worse. The premise is since cancer cells die when they lose their blood supply (as evidenced by the existence of tumor necrosis), cutting off the blood supply may be the best means of killing the tumor. If you can cut off the blood supply at the outside edges of the tumor, all cells below will die. Therefore, tumor mass penetration is not a problem, its a benefit.
The VTA technology grew out of the anti-angiogensis research field. The anti-angiogensis inhibitors attempt to stop the cancer cell's ability to hijack the body's ability to build blood vessels. If a tumor cannot grow blood vessels, it cannot grow. In theory, you could keep the patient alive as long as s/he is taking the drug. The research around angiogenisis identified the factors that cause these cells to grow. VEGF (Vascular Endothelial Grow Factor) is the best known of these factors.
Dr. Thorpe's idea was to use an antibody (or other compound) to target a factor that starts the blood clotting cascade specifically to the tumor vessels. The antibody side is the targeting side. Dr. Thorpe has developed antibodies that target antigens that exist only on cancerous endothelial cells within the tumor. He then attaches truncated tissue factor to the antibody. When the antibody puts the tissue factor in direct contact with the endothelial cell it starts the blood-clotting cascade. The process is as follows: Tissue factor>VIIa>X>Xa>prothrombin>thrombin>fibrinogen>fibrin. The blood clotting cascade is a highly amplified, self-sustaining process. One molecule of tissue factor generates 250,000 molecules of thrombin and over 1 billion molecules of fibrin per minute. Therefore, a minute amount of drug can start a cascade that can block the whole blood vessel, killing all cells downstream of it.
Giving a tumor a stroke! Brilliant!
VASOPERMEATION ENHANCEMENT AGENTS
Vasopermeation Enhancement Agents (VEAs) are designed to make TNT and chemotherapy work better. Techniclone?s scientists discovered that you can specifically target vasoactive compounds (compounds that cause tissues to dilate) to tumors as a pre-treatment to therapy. The pre-treatment increases the permeability of the tumor blood vessels and capillaries allowing more of the therapeutic drug to enter the tumor mass, thus increasing the efficacy of the therapeutic treatment. The administration of the VEA pre-treatment provides a 2-hour window in which the uptake of the therapeutic dose can increase by up to 400%.
VEAs can be used to increase the efficacy of TNT and chemotherapy drugs. Vastly increasing the uptake of chemotherapy drugs should have a significant impact on the efficacy of these drugs, dramatically increasing their use. The use of VEAs as a pre-treatment would give doctors the choice of increasing the total amount of drug delivered to the tumor site to increase treatment efficacy or decreasing the amount of drug administered for treatment while maintaining the same efficacy profile. In essence, the doctor could choose to keep the drug toxicity level the same and have an increase in efficacy, or could choose to lower the toxicity of a drug while keeping the efficacy the same. Such a choice would be tremendously valuable to cancer patients and doctors.
Wow, increasing the efficacy or decreasing the toxicity of all chemotherapy drugs! What?s that worth to the big pharma companies who sell $7.6 billion every year in chemotherapy drugs?
TNT ? VTAs ?VEAs ? 2C3 -- SYNERGY.
TNT is the most advanced of TCLN's solid tumor cancer products. TNT has the ability to target any cancer that has necrosis (most if not all cancers). TNT carries a radioactive isotope to the tumor site, which then kills all tumor cells within a 300-cell radius. Each successive treatment creates more necrosis, thus more targets for the TNT antibody.
VEAs - Even though TNT can target necrotic tissue, which exists in all solid tumor cancers, tumors have structural barriers (poor blood supplies) which may limit the effectiveness of the treatment in some cancers (cancer specific and/or patient tumor specific). The VEA technology was designed to help TNT overcome the blood supply problem. VEA's are used as a pretreatment for the TNT therapeutic dose. For 2-3 hours after the administration of VEA, there will be an increase in the blood supply to the tumor and related cancer cells. During this "window" TNT with its radioactive isotope would be administered. The result should be greater uptake of the therapeutic dose, thus giving greater efficacy. VEAs are well suited as a pretreatment for all existing chemotherapy drugs.
VTAs choke off the tumor's blood supply altogether, causing massive necrosis. Although VTA's should be very effective, they will have their limitations (not being able to kill off a layer of cancers cells that get their blood supply from outside the tumor mass by seepage at the periphery of the tumor mass).
The massive amounts of necrosis created by VTA's make a perfect target for TNT. TNT could then be used to kill all remaining cancer cells at the periphery of the tumor. This one-two punch, could be the death of many, if not most, cancers.
2C3 stops the growth of tumor vessels (anti-angiogensis), thus halting the tumor in its tracks. Once the tumor is stopped from growing and the patient is stabilized, the TNT and or VTAs could be used to eradicate the tumor mass. If tumor eradication is not possible, 2C3 could, in theory, keep a patient alive for an indefinite period of time, hopefully until a cure is found.
Wow! These are some very innovative technologies that all work synergistically to kill solid tumor cancers. They are all owned by TCLN.
TNT, VTA & VEA PATENTS
THE TNT PATENTS cover the fundamental concept of targeting internal cellular antigens for all therapeutic and diagnostic applications for cancer.
THE VTA PATENTS cover the fundamental concept of vascular targeting, the fundamental concept of using clotting factors to initiate thrombosis, the concept of targeting VEGF to deliver drug to tumor vasculature, the use of tissue factor to initiate thrombosis, improved selectivity by targeting receptor/ligand complexes and other claims. The VTA patent portfolio consists of over 100 patents and licenses.
THE VEA PATENTS cover the fundamental concept of attaching vasoactive compounds to immunoactive fragments for the purpose of enhancing the uptake of therapeutic drugs or diagnostic agents.
MODIFIED ANTIBODIES TECHNOLOGY.
Techniclone scientists discovered that when a small organic molecule like the vitamin biotin is attached to a monoclonal antibody it decreases its electrical charge. Decreasing the electrical charge of the antibody dramatically influences the way the antibody travels in the blood stream. The positive electrical charge of an un-modified antibody gives it a ?sticky? characteristic that causes it to stick to capillary walls as it passes through the blood stream. This stickiness causes delayed antibody circulation, decreased tumor uptake and increased antibody clearance time (time it takes the antibody and toxic payload to clear from the blood stream). Increased clearance time results in higher toxicity.
Decreasing the antibody clearance time may dramatically reduce the toxicity of many, if not most, monoclonal antibody/toxic drug therapies. The increase in monoclonal antibody uptake at the tumor site should result in an increase in drug efficacy. Monoclonal antibodies using TCLN?s MAT clear from the bloodstream in half of the time of normal antibodies and produce a 2-3-fold increase in antibody/tumor uptake.
Wow, giving antibodies vitamins to ?pump them up?! A simple but very innovative idea that could be licensed to many companies developing monoclonal antibodies for therapy.
ONCOLYM--NON-HODGKIN?S B-CELL LYMPHOMA
Oncolym is a monoclonal antibody used in the treatment of intermediate and high grade non-Hodgkin?s b-cell lymphoma. Oncolym is currently in a Phase II/III clinical trial being conducted by Schering, AG. Oncolym is TCLN?s LYM-1 monoclonal antibody that targets the HLA-dr antigen (a very stable and abundant antigen site) that is present on at least 80% of all lymphomas. LYM-1 has the radioactive isotope iodine-131 attached to it that gives it tumor-killing capability.
In a previous Phase II, LYM-1/I-131 had a 56% complete + partial remission rate in the 54 patients treated in the study.
Schering, AG recently purchased the world-wide marketing rights for LYM-1 from TCLN and is responsible for conducting the U.S and European clinical trials for the antibody.
LYM-2
Techniclone?s scientists developed the LYM-2 antibody which targets a different antigen than LYM-1. The LYM-2 antibody works by causing the body?s immune system to attack the tumor. This treatment was designed to work on leukemias and lymphomas. Human clinical testing has not started for this antibody.
TCLN HAS THREE WORLD CLASS SCIENISTS!
Alan Epstein, M.D. Ph.D. Dr. Epstein received his M.D. from the Stanford University School of Medicine and his Ph.D. in cancer biology from Stanford University. He is a past recipient of the Hubert H. Humphrey Distinguished Research Award and the Searle Scholar Award to support his research activities. Dr. Epstein is the holder of seven patents and has published over 100 articles in the field of cancer research. Dr. Epstein is the inventor of TNT, VEAs, MATs, LYM-1 and LYM-2.
Philip Thorpe, Ph.D. Dr. Thorpe has worked in the cancer field for over a quarter of a century. His employment has included positions at the Institute of Cancer Research at the Royal Cancer Hospital, London, the Imperial Cancer Research Fund, London, the Department of Pharmacology and Therapeutic Oncology Research at the University of Texas Southwestern Medical Center, Dallas and he currently is the Director of Oncology Research and the Maine Medical Center Research Institute. Dr. Thorpe currently sits on the editorial review boards of the following publications: Antibody, Immunoconjugates and Radiopharmaceuticals; Bioconjugate Chemistry; Journal of Drug Targeting; Therapeutic Immunology and Angiogensis. Dr. Thorpe has over published over 140 articles in the field of cancer research and has 7 patents issued and three pending.
Clive R. Taylor, M.D., Ph.D. He hold positions as professor and chairman in the department of pathology at the University of Southern California. Currently, Dr. Taylor serves as an associate director of laboratories for the Los Angeles County Medical Center and is on the attending staff of the Kenneth Norris, Jr. Cancer Hospital and Research Institute. He received his M.D. degree from Cambridge University and his Ph.D. from Oxford University and is board certified by the American Board of Pathology in Anatomic and Clinical Pathology. He has been awarded numerous grants to engage in immunohistologic studies of various types of cancer and has authored more than 200 publications and ten books in the cancer field.
Three Brilliant scientists, one little company.
Postet on Yahoo's TCLN board 05/22/99 by Ownotshort There are many factors effecting the ability of Cotara to penetrate solid tumors. In theory TNT can target most any tumor because necrosis is a common characteristic of tumors. To understand how Cotara works, one must first take a short course in tumor biology. Dr. Rakesh Jane(sp?), from Harvard has published extensive papers on the structure of tumors. I believe his work was a spin off of Dr. Folkman's anti-angiogenesis research (as is Dr. Thorpe's VTA research).
In the simplest terms, all tumors the size of a pea have the ability to hijack the body's mechanism for growing blood vessels (angiogenesis). This is why tumors grow. The problem (thankfully) is that they are not very good at angiogenesis. They build very poor blood networks. Therefore, as the tumor grows, the cells that are further from the active growth area are slowly choked off of their blood supply. Losing the blood supply kills the tumor cells. This gives you necrosis.
Now you know how the necrosis is formed. Lets move to targeting TNT to the tumor. The ultimate goal of TNT targeting is to get within 300 cell layers of all parts of the tumor. If we can get within 300 cell layers the radiation will kill it. This is where the challenge is. Since there is a bad blood supply, TNT cannot get to all areas of the tumor, thus limiting its effectiveness. This is where Dr. Epstein pulls out the big guns. He developed the Vasopermeation Enhancement technology.
All of TCLN technologies are designed to work together as one powerful cancer treatment. Now, the idea is to pre-treat the tumor with the VE technology. The VE technology is simply TNT with a vasoactive compound. There are many vasoactive compounds IL-2,TNF and others. (TCLN has in fact developed a compound that is genetically engineered to isolate the vasoactive region of the IL-2 molecule.) These vasoactive compounds cause blood vessels and their walls (endothelial cells) to open up, letting more blood to flow through to the tumor cells. The literature states there is a 2-3 hour window of increased permeability. This is your window to inject the TNT/radioactive isotope compound. The more TNT that can bind to the deeper parts of the tumor, the more your going to see the tumor shrink.
Therefore, TNT is limited by its ability to access the necrotic regions of the tumor. You wouldn't expect to see TNT have a lot of efficacy with a tumor that has a poor blood network or does not have a lot of necrosis.
A poor blood network is the real hindrance to all cancer treatments. It effects chemotherapy and immunotherapies more than TNT. This is not necessarily do to the TNT antibody, but the radioactive isotope. The radioactive isotope can kill cells in a 300 cell radius. The beta rays emitted by the isotope damage the DNA, thus killing the cell and its ability to replicate. Since cancer cells are already weak, they are easier to kill than healthy cells (healthy cells can withstand more beta ray hits on the DNA than cancer cells).
For a chemotherapy drug to work, the compound must come in direct contact with the cancer cell to kill it. Therefore, the problem of poor blood supply makes it very difficult for a chemotherapy drug to kill tumors. Radioactivity is just a more efficient killer than a drug compound.
Until we can overcome the blood supply issue, radioactive isotopes may become the best type of therapy. There are several coming to the market.
How can you beat the blood supply problem, that?s the question?
Guess what, Dr. Thorpe may have found the answer. You gotta love it, TCLN acquired this technology for $25 million.
In the simplest terms, the Vascular Targeting Agent technology eliminates this issue altogether, in theory. The VTA technology in effect attempts to make the poor blood supply issue worse. The premise is since cancer cells die when they lose their blood supply (as evidenced by the existence of tumor necrosis), cutting off the blood supply may be the best means of killing the tumor. If you can cut off the blood supply at the outside edges of the tumor, all cells below will die. Therefore, tumor mass penetration is not a problem, its a benefit.
The VTA technology grew out of the anti-angiogenesis research field. The anti-angiogenesis inhibitors attempt to stop the cancer cell's ability to hijack the body's ability to build blood vessels. If a tumor cannot grow blood vessels, it cannot grow. In theory, you could keep the patient alive as long as s/he is taking the drug. The research around angiogenesis identified the factors that cause these cells to grow. VEGF (Vascular Endothelial Grow Factor) is the best known of these factors.
Dr. Thorpe's idea was to use an antibody (or other compound) to target a factor that starts the blood clotting cascade specifically to the tumor vessels. The antibody side is the targeting side. Dr. Thorpe has developed antibodies that target antigens that exist only on cancerous endothelial cells within the tumor. He then attaches a factor that when it comes in direct contact with the endothelial cell it starts the blood-clotting cascade. The blood-clotting cascade is a self-amplifying process. Therefore, a minute amount of drug can start a cascade that can block the whole blood vessel, killing all cells downstream of it.
In summary, Dr. Thorpe has developed a technology that has the ability create blood clots selectively within, and only within, tumor blood vessels.
Radioactive isotopes are millions of times more efficient killers than chemotherapy drugs, and blood clots are m(b)illions more efficient killers than radioactive isotopes. I think we've got cancer on the run now.
TCLN THE BIG PICTURE
TNT is the most advanced of TCLN's solid tumor cancer products. TNT has the ability to target any cancer that has necrosis (most if not all cancers). TNT carries a radioactive isotope to the tumor site, which then kills all tumor cells within a 300 cell radius. Each successive treatment creates more necrosis, thus more targets for the TNT antibody.
Even though TNT can target necrotic tissue, which exists in all solid tumor cancers, tumors have structural barriers (poor blood supplies) which may limit the effectiveness of the treatment in some cancers (cancer specific and/or patient tumor specific). The VEA technology was designed to help TNT overcome the blood supply problem. VEA's are used as a pretreatment for the TNT therapeutic dose. For 2-3 hours after the administration of VEA, there will be an increase in the blood supply to the tumor and related cancer cells. During this "window" TNT with its radioactive isotope would be administered. The result should be greater uptake of the therapeutic dose, thus giving greater efficacy. VEA's are about 1-3 years behind TNT.
VTA's choke off the tumor's blood supply altogether, causing massive necrosis. Although VTA's should be very effective, they will have their limitations (not being able to kill off a layer of cancers cells that get their blood supply from outside the tumor mass by seepage at the periphery of the tumor mass).
The massive amounts of necrosis created by VTA's make a perfect target for TNT. TNT could then be used to kill all remaining cancers cells at the periphery of the tumor. This one-two punch, could be the death of many, if not most, cancers.
These are some very innovative technologies that all work synergistically to kill solid tumor cancers. They are all owned by TCLN. |
