Celgene Corporation reported that data was presented at the annual meeting of the American Association for Cancer Research (AACR) demonstrating the anti-cancer and anti-inflammatory properties of its IMiD class of drugs in pre-clinical studies. Researchers from Celgene also presented data on the anti-proliferative properties of a novel third-generation selective estrogen receptor modulator (SERM) for the potential treatment of ovarian cancer.

The first study, a joint effort of scientists at Celgene and the Molecular Biology and Biochemistry department of the University of California at Irvine, evaluated the effects of two IMiDs on the expression of cell surface marker 69 (CD69) on natural killer (NK) cells. Flow cytometry analysis indicated that both IMiDs enhanced the expression of CD69 on NK cells by 64 per cent and 54 per cent respectively. These results suggest that IMiDs increased the expression of CD69 by enhancing the production of interleukin-2 (IL-2) by T-cells. The IMiDs increased transcriptional activity of transcription factors NF-kB and AP-1by 3- and 5-fold respectively. The study results demonstrate that the IMiDs exert their effects at least in part by acting on NF-kB and AP-1 pathways in T-cells to augment IL-2 production, thereby leading to enhanced activation of NK cells.

Celgene scientists presented a second study investigating the effects of two IMiDs on interleukin-10 (IL-10) production by either peripheral blood mononuclear cells (PBMCs) or purified monocytes and T-cells. Cells were pretreated with the IMiDs and stimulated with either lipopolysaccharide (LPS) for monocyte response, or anti-CD 3 or anti-CD 28 for T-cell response. Both IMiDs increased IL-10 production by PBMCs and purified monocytes by 2.8- and 3.2-fold respectively, when compared with LPS alone. Furthermore, the IMiDs enhanced IL-10 production in a dose-dependent manner.

"These findings further support our decision to initiate a broad clinical development program for the IMiDs," said David I. Stirling, chief scientific officer of Celgene Corporation. "Based on the compounds' immunomodulatory and anti-cancer properties, we will be initiating a number of clinical trials investigating their potential in serious inflammatory diseases and several cancers."

IMiDs are structural analogs of thalidomide that have significantly greater immunomodulatory activity in vitro while not demonstrating teratogenicity in animal models. In addition, in a Phase I trial with healthy volunteers, the IMiDs did not display thalidomide's sedative effect, a potential dose-limiting side effect. Two Phase I/II clinical trials in multiple myeloma were initiated for the IMiDs in 2000 at the Dana-Farber Cancer Institute and the University of Arkansas Cancer Research Center. The IMiD class of compounds are covered by multiple issued and pending patents in the U.S. and internationally.

In addition to the presentations on the IMiDs, scientists from the Signal Research Division of Celgene presented data from a study evaluating the in vitro anti-proliferative effects of a Celgene SERM-alpha compound, SPC8490, in ovarian cancer. SPC8490 is a novel SERM-alpha compound that effectively blocks MCF-7 breast cancer cell proliferation in vitro and tumor growth in animal models. SPC8490 is structurally different than tamoxifen, raloxifene and faslodex and does not demonstrate a stimulatory effect in uterine tissue, as do certain other SERMs. SPC8490 also has demonstrated improved efficacy over tamoxifen in breast and ovarian cancer cell lines and in tumor models.

Most recently, SPC8490 has been evaluated in a series of pre-clinical studies designed to establish its safety and suitability for use in humans. Phase I clinical trials are planned for later this year as part of Celgene's oncology development plan.

"We are very excited about the efficacy and safety profiles of our novel SERMs," said Alan J. Lewis, president of the Signal Research Division of Celgene. "Hormonally responsive cancers such as breast, ovarian and endometrial tumors will be natural targets for these drug candidates."