IL-1α (Interleukin-1, alpha)

Biology and Diseases

IL-1α and IL-1β are pro-inflammatory cytokines involved in immune defense against infection, and are part of the IL-1 superfamily of cytokines. Both IL-1α and IL-1β are produced by macrophages, monocytes and dendritic cells.

IL-1 is involved in various immune responses with a primary role in inflammation, making it a target for Rheumatoid Arthritis (RA). IL-1α and IL-1β are produced as precursor peptides, which are proteolytically processed and released in response to cell injury, and thus induce apoptosis. IL-1β production in peripheral tissue has also been associated with hyperalgesia (increased sensitivity to pain) associated with fever.

Therapies

Amgen currently markets Kineret (anakinra), a synthetic form of the human interleukin-1 receptor antagonist (IL-1Ra). IL-1Ra blocks the biologic activity of IL-l alpha and beta by competitively inhibiting IL-1 from binding to the interleukin-1 type I receptor (IL1-RI), which is expressed in a wide variety of tissues and organs. IL-1Ra inhibits the biological activities of IL-1 both in vitro and in vivo, and has been shown to be effective in animal models of septic shock, rheumatoid arthritis, graft versus host disease, stroke, and cardiac ischemia. Also in the Amgen pipeline is AMG 108, a fully human monoclonal antibody that targets inhibition of the action of interleukin-1 (IL-1). A Phase 2 clinical study is underway to assess long-term safety of treating rheumatoid arthritis with AMG 108.

Unmet Need

Elevated levels of IL-1α will continue to be a diagnostic target for inflammatory diseases like rheumatoid arthritis. Thus, there is a need for assays with sensitivity to quantify low levels of IL-1α in healthy subjects to differentiate between healthy and diseased states. Evaluation of IL-1α as a drug target presents a need to detect the velocity of decreases in elevated levels of IL-1α to evaluate effectiveness and dosing of potential therapies. This may prevent adverse events like neutropenia that develop after co-administration of drugs targeted to inflammatory cytokine pathways, like Kineret (IL-1Ra antagonist) and Enteracept (TNF-alpha antagonist). To meet these goals, it is essential to have an assay that can detect IL-1α to below normal levels in human plasma.

Singulex Answer

The Singulex IL-1α assay increases the utility of IL-1α by allowing quantification at very low levels and differentiation between small changes in concentration that can provide insights into drug efficacy or disease progression. The IL-1α assay has an LLoQ of 0.14 pg/mL and a reading range of 0.07-2000 pg/mL, enabling accurate quantification of IL-1α in human plasma with a broad dynamic range. The Singulex IL-1α Assay has also been validated for use in serum.

This assay will allow investigators to:

1. Measure the efficacy and dosing of therapeutics designed to interfere with the IL-1 mediated inflammatory response, such as Kineret.

2. Design more robust clinical and preclinical studies when IL-1α concentration can be used as a therapeutic endpoint, as in the clinical trial of AMG 108.

3. Understand how IL-1α levels change in patients as they transition from healthy to diseased states.

Application Note

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