Date: Thu, 18 Dec 1997 18:01:09 GMT Server: NCSA/1.5.2 Last-modified: Fri, 05 Dec 1997 15:34:31 GMT Content-type: text/html Content-length: 7693 Small Molecule Immunoregulators

Small Molecule Immunoregulators


T Cell Sciences aims to discover and develop novel small molecule immunoregulators that treat immune system, inflammatory and infectious diseases by stimulating or suppressing the immune response. Based on the company’s significant understanding of T cell-mediated immune responses and signal transduction pathways within lymphocytes, T Cell Sciences has developed:

  • High throughput assays to identify both immunosuppressive and stimulatory compounds
  • Broad-based mechanism of action assays to identify specific targets within pathways
  • Screening for small molecule immunoregulators using these assays is an ongoing drug discovery program at T Cell Sciences, conducted in partnership with pharmaceutical and biotechnology companies who provide drug development resources and/or compound libraries. The company has to date established access to synthetic compound and natural product libraries for screening through relationships with corporate partners ArQule and Repligen. In addition, T Cell Sciences has developed expertise in pharmacokinetics and pharmacodynamics, as well as animal models to demonstrate in vivo efficacy of its drug leads.

    The immunosuppressive molecules that T Cell has identified through this program have potential as treatments for transplant rejection, autoimmune disorders and inflammatory diseases. Immunostimulatory compounds discovered by the company are useful in the treatment of cancers, infectious diseases and as adjuvants that increase vaccine effectiveness.

    Economic Opportunities

    Significant economic opportunities exist for small molecule drugs that suppress or stimulate the immune response. Immunosuppressive drugs are currently used to prevent or treat transplant rejection or to treat chronic diseases such as rheumatoid arthritis that are associated with autoimmune disorders and/or inflammation. While current immunosuppressives such as cyclosporin A and FK506 are effective for certain indications such as organ transplantation, the toxicity of these drugs dramatically limits their market application in less life-threatening settings that require chronic drug use (e.g. as treatments for autoimmune diseases such as rheumatoid arthritis). Current worldwide sales of immunosuppressives are well in excess of $1 billion annually; experts estimate that the market potential for immunosuppressive drugs for use in transplantation alone will grow to $5 billion worldwide by 2010.

    Immunostimulants that boost immune responses against disease could provide new treatments for AIDS and other infectious diseases and cancer, as well as provide new adjuvants to increase the effectiveness of vaccines. Applications for immunostimulants extend to animal as well as human health.

    Platform Technology

    T Cell Sciences has created a platform technology for discovery of small molecule drugs that modulate key immune system pathways. The company’s discovery program is based on the use of several proprietary, stable lines of T cells that are suitable for high-throughput screening for immunoregulatory compounds that stimulate or suppress T cell activation. The T Cell lines are activated specifically through cell surface receptors (TCRs) using the company’s proprietary anti-TCR monoclonal antibodies. With this system, T Cell Sciences can access all potential targets along the signal transduction pathway leading to T cell activation, ensuring that any compound that regulates activation at a point along that pathway will be identified.

    T Cell Sciences believes that its receptor-mediated screening assays are superior in several ways to most other T cell activation assays:

  • Most other T cell assays activate T cells chemically, at a point in the activation pathway downstream from the TCR. Thus, immunoregulators that act at upstream signal transduction steps are missed by those assays.
  • Receptor-mediated assays also allow T Cell Sciences to identify compounds that regulate activation but have no effect on resting T cells. In contrast, calcineurin is involved in other cell functions besides activation; thus, compounds that act at this target may affect resting as well as activated T cells. Such compounds can produce unacceptable drug toxicities like those seen with cyclosporin A and FK506.
  • T Cell Sciences’ assays can identify both compounds that inhibit T cell activation and those that stimulate it. In contrast, chemically activated T cell assays can only detect immunoinhibitory molecules.
  • T Cell Sciences’ goal is to identify compounds that act through mechanisms different from calcineurin and that have no effect on resting T cells. In that way, the company hopes to discover new immunoregulatory drugs that avoid the toxicity associated with cyclosporin A and FK506.

    Results to Date

    T Cell sciences has established a variety of molecular and cellular assays of TCR-mediated signal transduction which are used to elucidate the mechanism of action of lead compounds in a rapid and consistent manner. To date, the company has isolated several lead immunosuppressive compounds from both the combinatorial and natural product libraries provided by its biotech corporate partners. For example, one of the compounds that T Cell Sciences has identified inhibits a mouse model of Delayed-Type Hypersensitivity in a dose dependent manner, with a dosage of 1.0 mg/mouse giving a comparable efficacy to cyclosporin dosed at 2.0 mg/mouse.

    T Cell Sciences has also identified two classes of immunostimulators from its screening program. One class augments the early stages of T cell receptor activation, leading to enhanced T cell proliferation as well as IL-2 expression; the other prevents activated T cells from undergoing apoptosis, therefore leading to a prolonged T cell response. The different mechanisms of action for these two classes of immunostimulators make them potentially useful for different clinical targets.

    Updated December 3, 1997


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