BOTHELL, Wash.--(BUSINESS WIRE)--April 8, 2003--Seattle Genetics, Inc. (Nasdaq:SGEN - News) today reported data from its antibody-drug conjugate (ADC) research programs.
Three abstracts describing these findings were published in the 2003 Proceedings of the Annual Meeting of the American Association for Cancer Research (AACR) and were to be presented during that organization's recently cancelled annual meeting in Toronto, Canada.
"These data demonstrate some of the significant advances that scientists at Seattle Genetics have made with our ADC technology," stated Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. "We dedicate substantial efforts to the research and development of ADCs because we believe that arming antibodies with cell-killing payloads will continue to emerge as an important technology for increasing the potential of antibody-based therapeutics. Our ADC technology enables us to develop product candidates for our own pipeline and creates opportunities to partner with other companies developing targeted therapeutics."
"Our research illustrates how each component of an ADC contributes to therapeutic efficacy," added Peter D. Senter, Ph.D., Vice President of Chemistry at Seattle Genetics. "This includes the targeting ability of the antibody used for delivery, the potency of the drug that is delivered and the stability of the linkers that attach the drug to the antibody."
Poster presentations with additional information on the following research programs can be accessed on Seattle Genetics' website, www.seattlegenetics.com, under "technology".
Anti-Cancer Activity of High-Potency Anti-CD20 Antibody-Drug Conjugates (Abstract #769)
The anti-CD20 monoclonal antibody rituximab (Rituxan®) is efficacious in the treatment of B cell malignancies, most notably non-Hodgkin's lymphoma. Although conjugation to radioisotopes has been shown to increase the effect of anti-CD20 therapy, anti-CD20 ADCs have not previously demonstrated antitumor efficacy, possibly due to inefficient internalization of the mAb within tumor cells.
Seattle Genetics has conducted in vitro and in vivo studies demonstrating the antitumor activity of anti-CD20 monoclonal antibodies (mAbs) conjugated to a proprietary, highly potent variant of Auristatin E, a cell-killing drug that is part of the company's leading ADC technology. The drug, monomethyl Auristatin E (MMAE), was chemically attached to anti-CD20 antibodies by an enzyme-cleavable linker that is stable in blood and allows for the drug to be released upon conditions present within target cells. While studies of rituximab on its own showed diffuse surface localization following binding to CD20, the rituximab ADC was found to internalize within target cells. Once inside the cell, MMAE was released and induced cell death. By comparison, anti-CD20 mAbs conjugated to the chemotherapeutic drug doxorubicin did not show substantial internalization and were ineffective.
These data indicate that anti-CD20-based ADCs may be effective antitumor agents if conjugated to cell-killing drugs using Seattle Genetics' leading ADC technology.
SGN-35, an Anti-CD30 Antibody-Drug Conjugate with Potent Antitumor Activity (Abstract #770)
Seattle Genetics has conducted preclinical studies demonstrating the potent antitumor activity of the company's ADC, SGN-35, against CD30-expressing hematologic malignancies. SGN-35 is comprised of an anti-CD30 mAb chemically attached by an enzyme-cleavable linker to a highly potent variant of the drug Auristatin E (MMAE). The CD30 antigen is highly expressed on the surface of hematologic malignancies, including Hodgkin's disease, anaplastic large cell lymphoma (ALCL) and some other types of lymphoma and leukemia. On normal cells, CD30 expression is limited to a subset of activated lymphocytes, making it an attractive target for antibody-based therapeutics.
In vitro studies demonstrated that SGN-35 remains stable after incubation in human plasma for greater than ten days, but that the linker is efficiently cleaved upon internalization of the ADC into the target cell, where active drug is released and results in cell death. In vivo studies further demonstrated that SGN-35 is efficacious in both disseminated and subcutaneous models of Hodgkin's disease and ALCL, with complete regressions and cures at doses as low as 1 milligram per kilogram. SGN-35 was also found to be well-tolerated in mice at doses considerably higher than those required for complete regression of tumors in preclinical models.
The high potency, stability and substantial therapeutic window suggest that SGN-35 has significant clinical potential for the treatment of CD30-expressing hematologic malignancies.
Potent Monoclonal Antibody-Drug Conjugates: The Role of Linker Stability in Efficacy, Toxicity and Specificity (Abstract #6425)
Seattle Genetics is investigating a class of highly potent drugs known as auristatins for use in its ADC technology. These drugs have been prepared with appended linkage systems that allow for active drug release either under acidic conditions or by enzymes present within target cells. Seattle Genetics conducted studies showing that ADCs prepared with hydrazone linkers for acid-mediated drug release were highly active in vitro and in vivo, yet demonstrated instability in human and mouse plasma. Another series of ADCs were prepared using enzyme-cleavable linkers that are highly stable in plasma, but that are rapidly cleaved inside of cells by enzymes such as cathepsin B. These conjugates had more tumor specificity in vitro than corresponding ADCs utilizing hydrazone linkers and were less toxic in vivo. The stability in plasma coupled with the highly efficient release of active drug by intracellular enzymes suggest that there may be a wide therapeutic window for ADCs prepared with these enzyme-cleavable linkers. These studies underscore the importance of linker stability in developing therapeutic ADCs.
About ADCs
ADCs are monoclonal antibodies linked to potent cell-killing drugs. Seattle Genetics' ADC technology utilizes monoclonal antibodies that internalize upon binding to their cell-surface receptors. The environment inside the cell causes the cell-killing drug to be released from the monoclonal antibody, allowing it to have the desired effect. Until released, the cell-killing drug is inactive, thereby sparing normal cells. The company has developed a variety of linker technologies including enzyme-cleavable linkers that are very stable in blood and highly potent cell-killing drugs, such as variants of Auristatin E, which are synthetically produced and readily scaleable. Because the variants of Auristatin E are synthetic, the drug and linker can be prepared simultaneously as a drug-linker system, significantly simplifying the manufacturing process versus natural product drugs that are more difficult to produce and link to antibodies.
About Seattle Genetics
Seattle Genetics discovers and develops monoclonal antibody-based therapeutics to treat cancer and related diseases. The company has three platform technologies: engineered monoclonal antibodies, antibody-drug conjugates (ADCs) and antibody-directed enzyme prodrug therapy (ADEPT). Seattle Genetics has built a diverse portfolio of product candidates targeted to many types of human cancers, including two currently being tested in multiple ongoing clinical trials. Seattle Genetics has agreements with many organizations including Bristol-Myers Squibb, Genencor International and Medarex. The company also has license agreements for its ADC technology with Genentech, Celltech Group and Protein Design Labs (through its recent acquisition of Eos Biotechnology). More information about Seattle Genetics can be found at www.seattlegenetics.com. |
