Modulation of Immune Function by the Targeted Enhancement of CD154 Trimer Stability (25008)

Two lead compounds have been identified that can enhance immune function in vivo through a novel mechanism of stabilizing the CD154 trimer on the surface of activated T cells.

ADVANTAGES: The compounds are the first demonstrated to enhance immune function in this way. The molecules can be applied to:

Chemotherapeutic strategies -targeting and eliminating cancer cells. Standalone vaccines -protect against infectious or toxic agents. Treating infectious disease -antibiotic facilitator enhancing immune function. Facilitator for immune clearance of persistent infections. Boosting immune compromised individual immune responses.

BACKGROUND: The CD154 antigen (CD40L) is central to the induction of Th1 responses and immune effector function in the target site. Its expression is extremely transient and has been implicated in the induction of strong type 1 immune responses. CD154 on the activated T cell binds CD40 on the antigen presenting cell, resulting in co-stimulatory signals to that antigen presenting cell and induction of chemical messengers such as IL-12, and chemokines.

The aim of this study was to develop a new therapy for either inhibiting immune cell function in autoimmune disease, or enhancing natural or vaccine facilitated immune responses. The identification of a small molecule that can enhance immune responses in this way is the first successful scientific study to do so.

The process of discovering candidates began with docking studies using a molecular model of the CD154 trimer, identifying potential small molecule binding sites and screening over 250,000 compounds. Positive candidates were screened visually, and a small number were selected for in vitro testing of which two appeared to stabilize the trimer. In vivo studies using an autoimmune disease mouse model demonstrated that the two compounds accelerated disease onset in these animals, indicating their ability to enhance immune function in vivo. Additional in vivo studies currently being undertaken in a mouse cancer model indicate these compounds can reduce tumor size as well.

Type of Offer: Licensing

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