And part II....
By: golfdad97 $$$$
Reply To: 36390 by golfdad97 $$$$ Thursday, 5 Oct 2000 at 10:05 AM EDT
Post # of 36537
TCLN: Known prospects (rest of summary that RB truncated):
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 confirmed immediate shutdown of tumor vasculature that appears selective and does not affect normal vessels. Based on these observations, we have embarked on a phase I trial single IV dose of CA4P (on 10-min and 1-hr infusion schedules) at 3-wk intervals in pts with advanced cancer. A total of 66 cycles of therapy [in 19 pts (9M/10F)] have been given over 4 dose levels [18, 36, 60, 90 mg/m2 - 14, 8, 22, 6 (1-hr.), and 16* (12* cycles reduced to 60 mg/m2 after dose-limiting toxicity (DLT)] respectively. DLT has been seen at 90 mg/m2, including an episode of grade 3 pulmonary (shortness of breath) toxicity and a reversible episode (during cycle 2) of acute coronary ischemia (without sequelae and with preservation of normal myocardial function) thought secondary to coronary vasospasm. A variable symptom complex has been identified across all dose levels several hours following infusion and include faint flush, nausea and vomiting (which appears dose-related), and tumor pain. The side effect profile to date is suggestive of an agent with systemic vascular effects and devoid of other traditional cytotoxic effects (myelosuppression, alopecia and stomatitis). Preliminary MR perfusion estimation studies have demonstrated decreases in tumor blood flow. PK analysis in a single pt at 60 mg/m2 yielded for CA4P t1/2 of 9.7 min, t1/2 44.4 min, and AUC0–4h 15.9 µmol.h./L; for CA4 t1/2 of 9.3 min, t1/2 1.65 h, and AUC0–24h 30.4 µmol.h/L; and CAgluc t1/2 of 45.2 min, t1/2 4.01 h, and AUC0–24h 34.4 µmol.h/L. The drug is primarily metabolized by glucuronidation. A pt with anaplastic thyroid cancer has had a complete response. (This trial is supported by a clinical research grant from OXiGENE, Inc., Boston, MA.)
Scotia: Whoa…these poor guys got hit hard with the up and downs of trying to convince the FDA that their photodynamic therapy in head and neck cancer really doesn't burn up tissue. They have had meaningful clinical results that need to be pursued, and perhaps the specific delivery maybe offered by VTA can help their cause.
TECHNICLONE AND SCOTIA PHARMACEUTICALS SIGN LETTER OF INTENT TO LICENSE THE USE OF VASCULAR TARGETING AGENTS WITH PHOTODYNAMIC THERAPY
Tustin, CA. April 4, 2000 - Techniclone Corporation (NASDAQ:TCLN) today announced that the Company has committed to completing a licensing agreement for a segment of its Vascular Targeting Agent (VTA) technology, specifically related to applications of Photodynamic Therapy agents (PDT) with Scotia Pharmaceuticals Limited. The terms of the deal have not been disclosed but involve a licensing fee, milestone payments and a royalty upon commercialization of a product. Scotia has signed a binding letter of intent with Techniclone for the worldwide exclusive rights to this area. 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 PDT agents alone have been shown to be effective in treating some forms of cancer, the addition of a targeting agent as provided by the VTA technology could increase the utility of this therapeutic class of drugs. Techniclone holds the patents for attaching most therapeutic agents (including PDT agents) to vascular targeting agents for the purpose of killing the tumor. Scotia Pharmaceuticals is one of the leading PDT companies in the world. Scotia has developed the next generation of PDT agents which are more efficient and less toxic than their predecessors. PDT works by first loading the specific agents in tumor tissue. The agents are activated by applying light of specific wavelengths to the tumor causing the active agent to kill tumor cells. By using the VTA technology to target the tumor vasculature specifically, the combination with PDT agents could provide a method for getting more agent to the tumor with potentially greater selectivity. Dr. John Bonfiglio, Interim President, stated, "We are excited about working with Scotia in the Photodynamic therapy area. Scotia is a leading company in PDT therapy, and we believe the targeted delivery of this class of drugs may result in more effective and less toxic treatments for a wide variety of tumor types. Scotia has the expertise and resources to explore this promising area. This deal is another example of our strategy to leverage the VTA technology platform to maximize its commercial potential. Together with our other announced partnerships with Supergen and Oxigene we will continue to explore commercial development of the VTA platform technology. We will also continue to look for additional strategic partners in this area which complement our existing partnerships." "Scotia is excited by the opportunity to explore the combination of the VTA technology with our own proprietary PDT agents. We believe this combination could lead to an entirely new concept in how PDT therapies are administered and at the same time potentially broaden their application as useful treatments for cancer." stated Robert Dow, Chairman and CEO of Scotia Pharmaceuticals. "Scotia is an excellent company with highly innovative technology. We look forward to collaborating with Scotia to advance these new compounds to the market. The concept of combining the VTA technology with the PDT technology is extremely logical and should lead to exciting new product opportunities. The targeted delivery of PDT agents could improve the therapeutic index and safety profile of this promising class of drugs," stated Dr. Philip Thorpe of University of Texas Southwestern Medical Center at Dallas, inventor of the VTA technology.
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VEA: The vasopermeation enhancing techniques are evidently back-burner issues at the moment, but attractive enough for TCLN to pick up the licensing for this technology from USC.
Tustin, CA.- January 6, 2000 - Techniclone Corporation (NASDAQ:TCLN) today announced that the U.S. Patent Office has granted a US Patent #6007817 for Techniclone's Vasopermeation Enhancement Agent ("VEA") technology. The VEA technology is one of Techniclone's platform technologies, which will be used to enhance drug uptake in solid tumors. This broad patent covers the use of the VEA agents for the treatment of all solid tumors in conjunction with chemotherapeutic agents, monoclonal antibodies, cytokines and other therapeutic agents. The technology was developed to be administered prior to the administration of most existing cancer therapies. Preclinical studies in animal models have shown that drug uptake can be increased up to 400% in specific instances by using the VEA technology as a pretreatment.
This methodology can take several forms, depending upon the exact delivery system used to enter the tumor mass. It is designed to enhance the uptake of OTHER agents into the tumor capillaries, taking advantage of changes in the way the blood vessels allow permeation of molecules once the "dilating" agent is delivered. One such approach has been described by Epstein:
Cancer Res 1996 Nov 1;56(21):4998-5004
A chimeric Lym-1/interleukin 2 fusion protein for increasing tumor vascular permeability and enhancing antibody uptake.
Hu P, Hornick JL, Glasky MS, Yun A, Milkie MN, Khawli LA, Anderson PM, Epstein AL
Department of Pathology, University of Southern California School of Medicine, Los Angeles 90033, USA.
A murine antihuman B-cell monoclonal antibody, Lym-1, has shown considerable promise for the treatment of human malignant lymphomas. To enhance its clinical potential, a genetically engineered fusion protein consisting of a chimeric Lym-1 (chLym-1) and interleukin 2 (IL-2) was tested for mediating cytotoxicity, increasing vasopermeability, and enhancing antibody uptake in human malignant lymphomas. The chLym-1/IL-2 fusion protein, which was expressed initially in a baculovirus system and more recently in the glutamine synthetase gene amplification system, was shown to be processed and assembled into a normal immunoglobulin monomer with two IL-2 molecules per antibody. It was found to be equivalent to the chLym-1 antibody in antigen-binding specificity and relative affinity. In addition, it maintains IL-2 cytokine activity as demonstrated by support of T-cell proliferation. Moreover, in antibody-dependent cellular cytotoxicity assays against Raji target cells, chLym-1/IL-2 had approximately 2-fold and 4-fold higher cytotoxicity than chLym-1 and murine Lym-1, respectively. Used as a pretreatment, chLym-1/IL-2 enhances the uptake of chLym-1 at the tumor site by altering the permeability of tumor vessels producing tumor:normal organ ratios of 420:1 for blood and 1708:1 for muscle at 3 days. The in vitro and in vivo activities of chLym-1/IL-2, therefore, suggest that this genetically engineered antibody fusion protein may represent a new immunotherapeutic reagent for the treatment of human malignant lymphomas.
Identification of a monoclonal antibody, TV-1, directed against the basement membrane of tumor vessels, and its use to enhance the delivery of macromolecules to tumors after conjugation with interleukin 2.
Epstein AL, Khawli LA, Hornick JL, Taylor CR
Department of Pathology, University of Southern California School of Medicine, Los Angeles 90033, USA.
mAbs reactive with epitopes expressed on tumor vessels were evaluated as universal delivery agents of peptides with vasoactive properties to enhance the uptake of macromolecules in tumors. Unlike other reported approaches to target tumor vessels, a mAb designated TV-1 targets a basement membrane antigen that is found in all tissues but that is accessible only in tumor vessels, making it an alternative vehicle for the delivery of biologically active peptides to tumors. A panel of 30 monoclonal and polyclonal antibodies was screened by immunohistochemistry on sections of human tumors, normal vascular endothelium, and connective tissues. Five antibodies were chosen for in vivo evaluation, including two antifibronectin antibodies (TV-1, HFN 7.1), one anti-basic fibroblast growth factor antibody (anti-BFGF), and two antibodies reactive with a mesenchymal cell antigen (TP-1, TP-3). Three nude mouse tumor models characterized by varying degrees of vascularization (low to high) were used. After chemical conjugation to interleukin 2 (IL-2), these antibodies were used to pretreat tumor-bearing nude mice 3 h before injection with a radiolabeled mAb directed to the transplanted tumors. Pretreatment with TV-1/IL-2 or HFN 7.1/IL-2 produced a 3-fold higher tumor uptake of radiolabel compared to control mice pretreated with mAb alone. The other three vasoactive immunoconjugates failed to show significant increases in these tumor models. When TV-1/IL-2 was compared with the specific vasoconjugate (Lym-1/IL-2) as a pretreatment in the Raji lymphoma model, which has low vascularization, TV-1/IL-2 yielded approximately 60% of the tumor uptake seen with Lym-1/IL-2. In comparison, pretreatment with TV-1/IL-2 in the LS174T colon carcinoma model, which has high vascularization, yielded approximately the same tumor uptake seen with the B72.3/IL-2 vasoconjugate, which directly targets the tumor cells. These studies demonstrate that a mAb directed against fibronectin in the endothelial subcellular matrix can be used to deliver vasoactive agents to tumors. |
