Targretin Increases Susceptibility of Leukemic B- and T-Cells to ONTAK, In Vitro Study of Ligand Products Published in the Journal Blood Demonstrates.

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SAN DIEGO--(BUSINESS WIRE)--Aug. 29, 2002

Rexinoids Modulate Immune Response in CLL and Sezary Cells

Treating leukemic B- and T-cells with Ligand's (Nasdaq: LGND) bexarotene (Targretin(R)) made the cancerous cells more susceptible to killing by denileukin diftitox (ONTAK(R)), according to an in vitro study published by Tufts researchers in the most recent issue of the peer-reviewed journal Blood (Vol. 100, No. 4).

"This study demonstrates that bexarotene and other RXR modulators 'upregulate,' or make more plentiful, high-affinity interleukin-2 (IL-2) receptor expression on leukemic B- and T-cells, thus making them more susceptible to killing by denileukin diftitox," said co-author Francine Foss, M.D., associate professor of medicine and director of the lymphoma program at the Tufts New England Medical Center in Boston. "These results suggest that the clinical efficacy of ONTAK may be enhanced by adding Targretin to therapy, and Phase I/II trials to further elucidate this concept are underway."

IL-2 receptors are commonly expressed on the surface of cancerous cells. The receptor consists of three sub-units: p55 (also called IL-2R alpha or CD25), p75 (IL-2R beta/CD122) and p64 (IL-2R gamma/CD132). "High affinity" receptors are composed of all three sub-units. Previous in vitro studies have demonstrated that treatment with ONTAK, a genetically engineered fusion protein, is most efficient in leukemia and lymphoma cells expressing the high-affinity IL-2 receptor.

Targretin and other RXR modulators modulate immune response by binding to retinoid receptors within cells that play a role in regulating cell differentiation, growth and apoptosis. Targretin binds selectively to retinoid X receptors.

In the Blood study, the researchers exposed B- and T-leukemia cell lines and fresh leukemia cells to two low concentrations of bexarotene and alitretinoin (Panretin(R)) for 48 hours. Both bexarotene and alitretinoin up-regulated expression of p55 and p75 at least four-fold in T-cells and fresh leukemia cells. In B cells, bexarotene and alitretinoin increased expression of p75 but not p55.

The researchers then exposed the cells to denileukin diftitox, measuring protein synthesis inhibition and cell growth. Protein synthesis inhibition reflects the efficiency with which the diphtheria toxin portion of denileukin diftitox is internalized in cancerous cells. In T cells, protein synthesis was inhibited by 50-70% after exposure to bexarotene or alitretinoin. In B-cells, alitretinoin inhibited protein synthesis by 35%, compared to more than 50% with bexarotene. The researchers also measured cytotoxicity directly, and concluded that bexarotene enhanced the cytotoxicity of ONTAK more than alitretinoin did. Specifically, bexarotene increased the number of cells killed by ONTAK by between 23% and 48%.

Related News from Last Year's ASH Meeting

At the American Society of Hematology (ASH) meeting in December, Dr. Foss and colleagues demonstrated that treating cutaneous T-cell lymphoma patients with Targretin boosted the activity of ONTAK and increased patient response rates. The pilot Phase I/II study results showed that p55 expression increased in six of seven patients treated with 150 mg/day or more of Targretin for seven days, and that the overall response rate with the combination was approximately 75%. "Up-regulation of the IL-2 receptor occurred even at low doses of Targretin, and response rates exceeded those typically seen with either drug alone," Dr. Foss said.

About Targretin and ONTAK

In February 1999, the U.S. Food and Drug Administration (FDA) granted Seragen, Inc., a wholly owned subsidiary of Ligand, marketing approval for ONTAK for the treatment of patients with persistent or recurrent CTCL whose malignant cells express the p55 (CD25) component of the IL-2 receptor. In December 1999, the FDA approved Targretin capsules for the treatment of all stages of CTCL refractory to at least one prior systemic therapy.

About Ligand

Ligand discovers, develops and markets new drugs that address critical unmet medical needs of patients in the areas of cancer, skin diseases, men's and women's hormone-related diseases, osteoporosis, metabolic disorders, and cardiovascular and inflammatory diseases. Ligand's proprietary drug discovery and development programs are based on its leadership position in gene transcription technology, primarily related to Intracellular Receptors (IRs) and Signal Transducers and Activators of Transcription (STATs).

Caution Regarding Forward-Looking Statements

This news release may contain certain forward-looking statements by Ligand that involve risks and uncertainties and reflect Ligand's judgment as of the date of this release. Actual events or results may differ from Ligand's expectations. There can be no assurance that results of subsequent studies of ONTAK or Targretin capsules in combination with any therapy will confirm results presented here. Additional information concerning these and other risk factors affecting Ligand's business can be found in prior press releases as well as in Ligand's public periodic filings with the Securities and Exchange Commission, available via Ligand's internet site at www.ligand.com. Ligand disclaims any intent or obligation to update these forward-looking statements beyond the date of this release.

Full prescribing information for Ligand's products can be obtained in the United States from Ligand Professional Services by calling toll-free 800-964-5836, or on Ligand's internet site at www.ligand.com.

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