12:00 AM
Nov 12, 2009
 |  BC Innovations  |  Cover Story

Restoring immunosuppression in RA

Researchers at The Johns Hopkins University School of Medicine have identified a way to dial down excessive activation of T cells in rheumatoid arthritis and potentially other autoimmune diseases.1Amplimmune Inc. has in-licensed the IP and has a therapeutic in preclinical development that blocks activation of T cells before they can release proinflammatory cytokines; thus the compound works upstream of RA drugs that inhibit tumor necrosis factor-α (TNF-α).

Co-inhibitory and co-stimulatory molecules expressed on the surface of antigen-presenting cells (APCs) are essential for maintaining a balanced immune response that fights infection without triggering autoimmunity.2

Either enhanced co-stimulatory activity or impaired co-inhibitory activity can lead to the excess inflammation that is a hallmark of autoimmune diseases. Therefore, two avenues for reducing inflammation are antagonizing co-stimulatory pathways or agonizing co-inhibitory pathways.

RA drug Orencia abatacept from Bristol-Myers Squibb Co. takes the first road. The cytotoxic T lymphocyte-associated protein 4 (CTLA4; CTLA-4; CD152)-Ig fusion protein binds CD80 (B7-1) and CD86 (B7-2) on the surface of APCs to prevent those ligands from binding their receptors and stimulating the activity of T cells.

The Johns Hopkins group and Amplimmune are taking the latter route, agonizing a co-inhibitory pathway mediated by a molecule called v-set domain containing T cell activation inhibitor 1 (VTCN1; B7-H4).

Work by the Hopkins group and others previously implicated B7-H4 as an important co-inhibitory molecule in autoimmunity and cancer (see "Enhancing immunosuppression in RA").3-5Moreover, a rodent study showed that B7-H4 could exist in a soluble form during the proinflammatory response to ovarian cancer.6

As a result, the Johns Hopkins team hypothesized that soluble B7-H4 might be responsible for...

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