Golfdad gave us one of his monumental TCLN postings on RB this week. I think it well worth re-reading and adding to the SI archives. I re-post it here, with his permission,....
By: golfdad97 $$$$
Reply To: None Thursday, 5 Oct 2000 at 10:00 AM EDT
Post # of 36537
TCLN: Known prospects. Part I of II
ONCOLYM: Finally. Guess it is time to find out whether Schering's DD on this therapy will pay off. Studies have been published mainly by the DeNardo's over the past few years. The history of this antibody to NHL has been recently summarized at the following link:
ragingbull.altavista.com
The latest press release does not outline the sites proposed, nor have we really heard any plans about the possibility of combination therapy with the antibody. One would expect the Phase I should move very quickly, since they have tons of data on effects of single doses. The parameters described below should be rapidly determined.
TECHNICLONE ANNOUNCES PLANS FOR COMMENCEMENT OF ONCOLYM CLINICAL STUDY BY STRATEGIC PARTNER SCHERING AG Tustin, CA. - June 22, 2000 - Techniclone Corporation (NASDAQ:TCLN), announced today that Schering AG, Germany, its strategic partner for its Non-Hodgkins lymphoma drug, Oncolym®, will commence patient enrollment for the planned Phase I human clinical study shortly through its U.S. subsidiary Berlex Laboratories. This dose escalation study is designed to measure safety and efficacy of a single dose of Oncolym® in intermediate and high grade Non-Hodgkins Lymphoma. This study is designed to treat up to 18 patients with provisions to treat more if necessary. Initially, four clinical centers will be opened for this study which will be evaluating the dosimetry, biodistribution, safety and efficacy of Oncolym®. Following the successful completion of the Phase I study, Berlex will start a Phase II/III study designed to confirm the safety and efficacy in over 100 patients. This study will initially enroll approximately 28 patients, upon satisfactory analysis of this group, the trial will continue as a Phase III trial.
It will be interesting to see if TCLN is able to fashion some relevant publicity for the Conference in the next week regarding the sessions chaired by Epstein and DeNardos:
DeNardos and Epstein Chairing Conference Sessions:
Eighth Conference on Radioimmunodetection and Radioimmunotherapy of Cancer, Oct 12-14, 2000, Princeton, N.J. Session VI (Experimental Radioimmunotherapy, including Pre-targeting)on Friday, Chairpersons; Sally J. DeNardo and Alan L. Epstein; Sesson VIII (Clinical Radioimmunotherapy: Solid Tumors; Chairperson, Gerald L. DeNardo; Session IX (Panel Discussion on the Role of Dosimetry in Radioimmunotehrapy Planning; Sally J. DeNardo, Moderator.
Opportunity for them to say something of the history and clinical findings of Oncolym, since the DeNardos' published most of the data on the clinical use of Oncolym in NHL.
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COTARA THERAPY OF SOLID TUMORS: I believed that S. Patel was quite encouraging with his remarks on the internet interview for the use of Cotara in glioma, under strictly defined conditions of tumor volume and prior resection. Bonfiglio mentioned in his conference call that the scientists/clinicians would be given "incentives" to publish and present (which is academically silly). We await the submission of the Phase I data, let alone the Phase II trial results. I imagine that TCLN is pushing to present these results at appropriate conferences as they occur. Will be watching the Neuro-oncology Societies programs this fall and winter, and look for whether we have submitted to ASCO next spring (the deadline for ASCO abstract submission is approaching).
The Mexico data must be paltry, but assume it gives enough experience to file a worthy IND for solid tumors here in the U.S. One assumes they learned enough of dosing, distribution and specificity of localization into the tumors that the company can file for the Stanford and Mayo-based studies.
In this regard, the data from China seems under wraps. The Chinese are normally quiescent about their research, much of it being published in obscure Chinese and international journals. Thoughts about how the China data may being handled was summarized here:
ragingbull.altavista.com
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COTARA-BASED IMAGING OF SOLID TUMORS: I would think this portion of the technology could be carried out quickly. However, there are many effective imaging techniques and reagents in use. It is important to remember that clinical departments who scan, label and image tumors for both diagnosis, performing the therapy and assessing the benefit of therapy have their own devices, methods and techniques that are often unique to the institution and the investigator. In addition, many of the markers used to image and detect primary and metastatic tumors are rather safe, quick acting and fairly effective. This may be a tough area to break into…there has to be a unique advantage to the use of TNT-antibody based labeling of tumors. In other words, we are able to visualize liver mets quite well, detect bone metastasis, and the use of contrast agents and markers make this a very competitive field to enter. Some preclinical data is available and was presented by Epstein this past year at the AACR:
Genetically engineered derivatives of chimeric monoclonal antibodyTNT-3 for the imaging of solid tumors
Barbara Helena Biela, Hu Peisheng, Khawli A Leslie, Bao Thomas, Sharifi Jahangir, Alan L Epstein, Univ of Southern CA, Los Angeles, CA.
A novel approach to tumor targeting has been developed which utilizes monoclonal antibodies (Mabs) directed against common and abundant intracellular antigens accessible only in necrotic areas of tumors. Designated Tumor Necrosis Therapy (TNT), this targeting approach circumvents many of the limitations of Mab therapy directed against tumor cell surface antigens. To date three Mabs have been chimerized which specifically target animal and human tumors but do not localize to normal tissues. In order to develop an imaging agent against solid tumors, genetic engineering methods were used to produce faster clearing single chain, diabody, triabody, Fab, and F(ab')2 antibody derivates of chTNT-3, MAb directed against single stranded DNA and cytoplasmic RNA. Each of the constructs were mass produced in NSO mouse myeloma cells using the glutamine synthase expression system and purified with either histidine or streptavidin affinity columns. First pharmacokinetics clearance data were obtained than using these results, biodistribution and imaging studies were performed in Madison 109 lung carcinoma bearing Balb/C mice. By genetically engineering derivatives from the same MAb, it was possible to compare the imaging capabilities of each construct in order to identify the best imaging agent for cancer detection. The results showed that derivatives based on the single chain (single chain, diabody, and triabody) were cleared rapidly with little tumor uptake at 6, 12, and 24 hr. The F(ab')2 fragment did show good specific targeting and tumor uptake at 24 hr. Additional studies will be undertaken to modify clearance pattern and uptake into tumor of this promising agent in a view of its future application for the imaging of human tumors in clinical settings.
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VTA (PART I): Vascular targeting almost needs no praise at the moment. It is the way of the future as one of three major directions of modern cancer therapy (antiangiogenesis, targeting of specific genetic requirements of clonal populations of tumor cells and potential gene therapy of cancers with a monospecific genetic defect).
Antiangiogenesis (the inhibition of new blood vessels) differs somewhat from vascular targeting (killing of tumor blood vessels that already exist). Philip Thorpe has developed an elegant approach to this latter technique as well as sizable and somewhat secure patent estate owned by TCLN. He published his original findings on the targeting of tumor blood vessels with a antibody construct that carried "tissue factor", a clotting molecule that caused vascular collapse of animal tumors several years ago…and probably only through the funding of ARCUS (perhaps), or via additional licenses not pursued by ARCUS does it seems these studies will get into the clinic. In my opinion, this is the single most important area to get into patient trials immediately. The potential of targeting molecules is immense, and they need to get with it. This approach was recently discussed by Thorpe at the prestigious Keystone conference:
DR. PHILIP THORPE GIVES PRESENTATION ON TECHNICLONE'S VASCULAR TARGETING AGENTS AT KEYSTONE CONFERENCE
Tustin, CA.- March 22, 2000 - Techniclone Corporation (NASDAQ:TCLN) today announced that Dr. Philip Thorpe Professor of Pharmacology at the University of Texas Southwestern Medical School at Dallas and inventor of the Vascular Targeting Agent ("VTA") technology, presented an update on new developments in his laboratory with this technology at the Keystone Conference held in Salt Lake City recently. Techniclone holds the exclusive worldwide license for this technology from the Board of Regents of the University of Texas system. Dr. Thorpe's presentation entitled "Targeting Coaguligands to Tumor Vasculature" examined the use of several agents designed to treat solid tumors by binding to the tumor blood vessels and subsequently causing a blood clot to form killing the tumors. These so-called "coaguligand" VTA molecules have shown efficacy in several mouse tumor models and are part of the technology that will be examined by the recently announced joint venture with Oxigene Corporation. Specifically, Dr. Thorpe presented anti-tumor experiments performed using coaguligands made by linking antibodies targeted to tumor vasculature markers such as Vascular Cell Adhesion Molecule-1 (VCAM-1) to a truncated version of the human coagulation protein, tissue factor. Once the coaguligand has localized to the tumor blood vessels, a blood clot is formed which results in occlusion of the blood vessel and starvation of the tumor cells. An important finding of the studies was that in order for the coaguligand VTA to be able to induce the formation of blood clots, a second marker known as phosphatidylserine (PS) must also be expressed on the cells that line the tumor blood vessels. "Our experiments have shown that there is the potential for an added margin of safety using these agents therapeutically. It appears that not only is it necessary to have a tumor specific target on the blood vessel but also PS must be present in order for the coagulation process to occur," stated Dr. Phil Thorpe. "This should accelerate the clinical testing of these new drugs" he further stated. The VTA technology was developed to be used as a front-line therapy or in conjunction with other cancer therapeutic agents for the treatment of solid tumors. Preclinical studies, such as those presented at the Keystone meeting, have shown in animal models that treatment with a VTA therapeutic agent can result in significant anti-tumor effects and, in some cases, in complete remission of the treated tumor. The VTA technology targets tumor vasculature to kill the tumor by depriving it of oxygen and essential nutrients. VTA act on the mature blood transporting vessels of the tumor. In contrast, antiangiogenisis agents prevent new tumor blood vessels from growing. These agents in theory could be used together to treat cancer. Techniclone holds over 50 patents either allowed, issued or pending in this area and plans to continue to look for licensing partners for areas in which the Company or the Joint Venture with Oxigene chooses not to focus.
The argument that Oxigene or ARCUS will develop the direct VTA of Thorpe is strengthed by statements of the Oxigene agreement, released in July of this year and shown below:
TECHNICLONE AND OXiGENE ANNOUNCE ISSUED BROAD CLAIMS ON VASCULAR TARGETING AGENTS WITH COAGULANTS
Tustin, CA, Boston, MA, Stockholm, Sweden - July 25, 2000 -Techniclone Corporation (NASDAQ:TCLN) and OXiGENE, Inc. (NASDAQ:OXGN) today announced the issuance of U.S. Patent No. 6,093,399 entitled “Methods and compositions for the specific coagulation of vasculature”. This patent broadly covers Vascular Targeting Agent ("VTA") compositions that include a coagulation factor. VTA technology is a platform technology for the treatment of solid tumors based upon agents that specifically disrupt tumor blood vessel function, which deprive tumors of oxygen and nutrients and cause greatly increased tumor cell death. VTAs involving coagulants safely and effectively prevent blood flow to a tumor in a site-specific manner through a controlled thrombolytic cascade resulting in a fibrin plug which blocks the tumor vessels. Techniclone and OXiGENE have formed a joint venture company, ARCUS Therapeutics, LLC, to develop this VTA technology. The newly issued patent consolidates ARCUS’ exclusive coverage of Vascular Targeting Agent compositions comprising coagulation factors and complements their earlier broad claims (e.g., U.S. Patent No. 5,855,866) directed to the delivery of all therapeutic agents to the blood transporting vessels of a tumor. The latest patent particularly covers a wide range of targeted coagulant compositions (coaguligands), including diverse targeting components and a variety of agents that directly or indirectly cause blood clots, specifically within tumor vessels. Arcus’ VTA technology, now protected by over sixty issued, allowed or pending U.S. and international patents and patent applications, was developed for use as either front-line therapy or in conjunction with other anti-cancer therapeutics for the treatment of solid tumors. Preclinical studies in animal models have shown that treatment with a VTA "coaguligand" can result in significant anti-tumor effects and in some cases complete remission of the treated tumor.
"Our current development plans include the use of the coaguligand technology in our first generation clinical candidates and this patent will insure that we are thoroughly protected from infringement by other companies" stated John Bonfiglio, Ph.D., Techniclone's President. Björn Nordenvall, M.D., Ph.D., President and CEO of OXiGENE said, “We are pleased with the a ccomplishments made by the joint venture in protecting the intellectual property of VTAs. We are now in a firm position to develop these drugs to treat cancer as we currently have done with our flagship VTA, Combretastatin A4 Prodrug, recently licensed to Bristol-Myers Squibb.” The VTA technology was invented by Philip Thorpe, Ph.D., who stated, “This patent is helpful in defining the uses of the coaguligand VTA area. The use of coaguligand VTAs with endogenous human coagulation factors is particularly exciting as it employs an entirely human therapeutic to destroy cancer.”
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VTA (PART II): The targeting of tumor vasculature is taking other forms by the company. The most awaited, I suppose, is the deal by Supergen. I imagine it is bogged down in the endless hassle of money (of course), but also by carefully defining the economic control of patents related to anything that uses, or targets VEGF, the all important growth and survival factor of endothelial cells. From the press release of last January, we know that Supergen plans to assault the tumor blood vessels by a "trojan horse" technique of attaching toxic molecules to the VEGF protein, which then will bind the receptor found on tumor endothelium (and some normal cells). This is given by the following statements from that release:
" The VTA technology is Techniclone's proprietary therapeutic platform designed to specifically target tumor vasculature and subsequently destroy the tumor with various attached therapeutic agents. Although VEGF alone is being examined by many companies as a target for anti-angiogenisis agents, Techniclone holds the patents for attaching most therapeutic agents to VEGF for the purpose of targeting them to the tumor vasculature. Dr. Philip Thorpe, (Professor of Pharmacology at the University of Texas, Southwestern Medical Center at Dallas and the inventor of the VTA technology has shown proof of principle with this technology in several animal models which have been published in peer reviewed scientific journals, including Science in 1997."
The best candidates for this type of approach can be deduced from the Thorpe coauthorship of studies presented at AACR concerning M. Rosenblum's studies on VEGF-gelonin, a construct that has good preclinical data in animal models:
IN VITRO AND IN VIVO STUDIES OF VEGF121/rGEL FUSION TOXIN TARGETING TUMOR NEOVASCULATURE.
Lawrence Cheung, Liesbeth Veenendaal, John W Marks, Sophia Ran, Philip Thorpe, Michael G Rosenblum, M D Anderson Cancer Ctr, Houston, TX; Univ of Texas Southwestern Med Ctr, Houston, TX.
Development of new blood vessels is essential to the growth and metastatic spread of solid tumors particularly breast, prostate and melanoma. VEGF plays a central role in tumor neovascularization. The VEGF receptors KDR/flk-1 and flt-1 appear to be restricted to activated endothelial cells with the highest expression found in the vasculature of solid tumors. Interference with this process is a promising strategy to inhibit tumor growth. We designed a fusion construct of VEGF121 and the highly cytotoxic plant toxin gelonin (rGel). The cDNA for VEGF121 was fused to the cDNA encoding rGel using PCR. The two molecules were tethered using the flexible linker G4S. The soluble VEGF121/rGel protein was expressed in bacteria and purified to homogeniety. The fusion construct migrated as an 82 kDa dimer under non-reducing conditions. Elisa assay studies demonstrate specific and competitive binding to receptor-positive but not receptor-negative cells and to isolated immobilized flk-1. In a cell-free protein synthesis inhibition assay, the VEGF121/rGel was several fold more active compared to native rGel. Against ABAE cells in culture, the fusion construct was 10 fold more cytotoxic than rGel (I.C.50= 59pM vs 524pM, respectively). In nude mice bearing well-established (subQ) A-375 human melanoma tumors, iv treatment (q 48 hr X 5) with total doses up to 17 mg/kg resulted in impressive suppression of tumor growth compared to controls. These data suggest that this construct has potential for clinical use and pre-IND studies are progressing. Research conducted, in part, by the Clayton Foundation for Research.
A recent seminar by M. Rosenblum outlined several new constructs designed to take this same approach targeting the VEGF receptor, but using different toxic molecules.
-----------------------------------------------------------VTA (PART III): The Oxigene partnership carries ramifications into big pharma. The lead oncology product of OXGN, combretastatin, has been found to have interesting clinical potential, but some non-specific toxicity. It may be that they are interested in specific vasculature delivery of this agent via a Thorpe-derived antibody, or will pursue the next generation of these microtubule inhibitors that are coming out of preclinical studies.
A Phase I Pharmacokinetic (PK) Study of Single Dose Intravenous (IV) Combretatstatin A4 Prodrug (CA4P) in Patients (PTS) with Advanced Cancer. S C Remick, A Dowlati, J Lewin, K Robertson, V Makkar, B Overmoyer, T Spiro, C Connell, N Levitan, C Buchter, B Stambler, A Taylor, M. Stratford, Ireland Cancer Ctr at Univ Hospitals of Cleveland, Cleveland, OH; Case Western Reserve Univ, Cleveland, OH; Gray Lab, Mt Vernon Hosp, London, UK.
CA4P disodium phosphate is a novel anti-tumor vascular targeting agent, which is the first of a series of combretastatin (CA4) analogs to enter the clinic. CA4P is rapidly dephosphorylated to the active compound CA4, which has a broad range of cytotoxicity in preclinical models. The drug binds the colchicine-binding site on tubulin, and inhibits mircotubule assembly. Animal studies have confi |
