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Radioimmunotherapy for NHL February 1998 Techniclone Corp. reported on the status of Oncolym, the companys most advanced drug development program. Oncolym is an investigational radioimmunotherapy being studied for the treatment of intermediate- and high-grade non-Hodgkins B-cell lymphoma. Techniclone Corp. is dedicated to the rapid and efficient development and commercialization of Oncolym to improve the quality of life for those people afflicted with this life-threatening disease. Oncolym Oncolym, a radiolabeled murine monoclonal antibody, is an investigational radioimmunotherapy being studied for the treatment of intermediate- and high-grade relapsed or refractory B-cell non-Hodgkins lymphoma. Iodine-131 is a radioactive form of iodine. When radioactive iodine-131 is attached to the Lym-1 antibody, the result is 131I Lym-1 or Oncolym. The antibody has a high specificity for human lymphoma cells. The radiolabeled antibody binds to the tumor after injection and appears to selectively kill the tumor cells by irradiation. Preliminary Clinical Results to Date To date, 88 patients have been treated with a therapeutic dose of Oncolym. In these trials, patients have achieved meaningful complete and partial remissions of their tumors. An overall response rate (complete and partial responses) of 41% has been demonstrated in patients with intermediate- or high-grade non-Hodgkins lymphoma. Non-target organ radiation dosimetry demonstrates a tolerable safety index. Side effects such as thrombocytopenia (low platelets) and leukopenia (low white blood cells) have been observed. Clinical studies have revealed that the side effects appear to be reversible and manageable and to have resolved without complications. Current Development Plans The current Phase II/III protocol includes all the claims for the intended labeling currently anticipated by Techniclone. The U.S. Food and Drug Administration (FDA) will need to review all clinical data to confirm all findings before Oncolym is cleared for marketing. Oncolym is being investigated as a treatment for patients that have failed two prior chemotherapy treatments and will be only for patients with intermediate- or high-grade relapsed or refractory non-Hodgkins B-cell lymphoma. Two therapeutic doses of 60 mCi/m2 of radiolabeled Lym-1 given 6-weeks apart will constitute a treatment cycle. There are no restrictions for prior chemotherapy regimens and in many cases, patients may be able to be treated in outpatient facilities rather than in the hospital. The company continues to remain on schedule to begin multi-center clinical trials in first quarter 1998. Non-Hodgkins Lymphoma (NHL) Non-Hodgkins lymphoma is a malignant (cancerous) growth of cells in the lymph system. The lymph system is a connecting network of glands and vessels, which manufacture and circulate lymph throughout the body. According to the American Cancer Society, an estimated 61,000 new cases of lymphoma will be diagnosed, including 7,500 cases of Hodgkins disease and 54,000 cases of non-Hodgkins lymphoma. Among the classified non-Hodgkins lymphoma disease group, approximately 65% of the patient population will be diagnosed with intermediate- or high-grade lymphoma. Prevalence of NHL includes over 200,000 patients in the United States and the incidence of patients with intermediate- or high-grade lymphomas who will fail chemotherapy and radiation is approximately 40,000. Oncolym is currently being investigated for treating intermediate- and high-grade NHL patients from whom current therapy has proven inadequate, and represents a major unmet medical need. Disease Grades Non-Hodgkins lymphoma (NHL) is sub-divided into three different grades based upon specific disease characteristics: low-grade, intermediate-grade and high-grade. Low-grade lymphoma affects about 35% of the patients newly diagnosed with the disease. Low grade lymphoma usually presents as a nodal disease. In a number of cases, low grade NHL can be indolent or slow-growing. Survival from the time of diagnosis with low-grade disease averages 5 to 7 years. Recent approval of a biologic therapy for low-grade disease was based on a combined overall response of 50%, which was considered similar to conventional therapy. Intermediate- and high-grade disease affects some 65% of the newly diagnosed cases of NHL and has average survival rates of 2-5 years in intermediate and six months to 2 years in high-grade disease. Intermediate-and high-grade disease usually presents as a much more aggressive disease with large extranodal bulky tumors. The large tumor bulk in intermediate- and high-grade challenges the development of radioimmunotherapy. Lym-1 Antibody When radioactive iodine-131 is attached to the Lym-1 monoclonal antibody, the result is 131I Lym-1 or Oncolym. The Lym-1 antibody is a murine IgG2a monoclonal antibody (MAb) raised against Raji cells, a malignant line cultured from Burkitts lymphoma. The Lym-1 antibody recognizes HLA-Dr10 protein, a cell surface marker present on over 80% of lymphoma cells. Only about 2% of the normal population have B-cells that express the HLA-Dr10 marker. This means that the Lym-1 monoclonal antibody may selectively target lymphoma cancer cells and may spare healthy B-cells that are responsible for making antibodies that fight infection. In addition, Lym-1 has high precision for its target receptor and may bind 5 times more avidly to lymphoma cells than to healthy cells that express the HLA-Dr marker. It is speculated that the HLA-Dr marker does not modulate (or go away) when treated and it does not come off the cell during treatment. The antibody profile for Lym-1 demonstrates high specificity only for lymphoma cells and binds to a very high degree to lymphoma cells rather than healthy cells. Numerous other investigations of both non-labeled and radiolabeled monoclonal antibodies that attach to the CD-20 cell surface receptor are currently underway. The CD-20 cell surface receptor protein is highly expressed on both mature healthy and lymphoma cells. As with Lym-1, anti-CD-20 antibodies have a high precision (or binding avidity) for their target surface receptor. However, since CD-20 is present on both healthy and lymphoma cells, therapies targeted at this marker have been shown to kill not only the lymphoma cells but also the healthy mature B-cells that normally help protect the body from infections. Techniclone chose the Lym-1 monoclonal antibody because the company believes that Lym-1 has the high precision associated with anti-CD-20 antibodies but also is more specific in recognizing and attaching to cancer cells while not attaching to healthy disease-fighting B-cells. Iodine-131 Radionuclide Techniclone Corp. uses iodine-131, a radioactive form of iodine, attached to the Lym-1 monoclonal antibody. Techniclone believes that iodine-131 appears to have a number of advantages as a therapeutic radionuclide. The primary potential advantage is that beta irradiation (the energy that kills the cancer) emissions from the isotope penetrate several millimeters killing some 300 cells around the antibody. This makes the radioimmunoconjugate very effective against the outer rim of cells in the tumor as well as against the bulk of the disease. It is this outer rim that causes the invasive damage of the tumor in bulky disease. Other potential advantages are that iodine is cheap to produce, abundant, requires simple radiolabeling procedures, has a long half-life, has well-characterized dosimetry and can be imaged. Other radioimmunoconjugates under investigation include yttrium-90 in combination with a monoclonal antibody to treat lymphoma. Techniclone has not pursued yttrium because this isotope is costly (approximately 10 times that of iodine-131), requires metal-chelation technology, has a short half-life, can not be imaged in its therapeutic form, and has such high energy that it may be less able to kill residual cancer at the tumor site. In addition, this higher energy may cause radiation damage to non-targeted tissue well away from the intended target. Dosing The current investigation for the treatment of intermediate- or high-grade NHL utilizes multiple therapeutic dosing to complete a treatment course. Data from a number of clinical trials with Oncolym in intermediate-and high-grade NHL suggest that patients with large bulky tumor may not respond as well to single doses of radiolabeled antibody compared to that observed with multiple dose treatments. This may be in part due to the inability of the limited amount of beta irradiation and short (a few millimeters) kill radius of iodine-131 to reach all cells in a large tumor when given as a single dose. Techniclone believes that radioimmunotherapy for intermediate- and high-grade NHL will require multiple doses to produce clinically meaningful effects. About Techniclone Techniclone Corp. is a biotechnology company focused on the research, development and commercialization of novel cancer therapeutics in two principal areas: 1) direct tumor targeting agents for the therapeutic treatment of refractory malignant lymphomas and 2) collateral targeting agents for the therapeutic treatment of solid tumors. Oncolym, the companys most advanced drug development program, is a radiolabled murine monoclonal antibody for the treatment of intermediate- and high-grade relapsed or refractory B-cell non-Hodgkins lymphoma. The company is developing additional product candidates derived from its collateral targeting program for solid tumor therapy: Tumor Necrosis Therapy (TNT), Vascular Targeting Agents (VTAs) and Vasopermeation Enhancement Agents (VEAs). TNT-1 is the first drug candidate to be clinically investigated from its collateral targeting program and is expected to begin Phase I clinical trials in first quarter 1998. Techniclone Corp. intends to establish strategic partnerships to rapidly develop and commercialize these products. For additional company information, visit the companys Web site at: http://www.techniclone.com
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