Interleukin1 biotechnology

IL-1 continues to be a focus of clinical investigation. This stems from its observed:

• immunostimulatory effects;

• ability to protect/restore the haematopoietic process during, or subsequent to, chemotherapy or radiation therapy;

• anti-proliferative effects against various human tumour cell lines grown in vitro, or in animal models.

Most of these effects are most likely mediated not only directly by IL-1, but also by various additional cytokines (including IL-2) induced by IL-1 administration. The observed effects prompted initiation of clinical trials assessing IL-1's efficacy in treating:

• bone marrow suppression induced by chemo/radiotherapy;

• various cancers.

The initial findings of some such trials (involving both IL-1a and IL-1P) proved disappointing. No significant anti-tumour response was observed in many cases, although side effects were commonly observed. Virtually all patients suffered from fevers, chills and other flu-like symptoms. More serious side effects, including capillary leakage syndrome and hypotension, were also observed and were dose limiting.

IL-1 thus displays toxic effects comparable to administration of TNF (see later), or high levels of IL-2. However, several clinical studies are still underway, and this cytokine may yet prove therapeutically useful, either on its own or, more likely, when administered at lower doses with additional therapeutic agents.

Because of its role in mediating acute/chronic inflammation, (downward) modulation of IL-1 levels may prove effective in ameliorating the clinical severity of these conditions. Again, several approaches may prove useful in this regard, including administration of:

• soluble forms of the IL-1 receptor;

• the native IL-1 receptor antagonist.

Kineret is the tradename given to a recently approved product based on the latter strategy. Indicated in the treatment of rheumatoid arthritis, the product consists of a recombinant form of the human IL-1 receptor antagonist. The 17.3 kDa, 153 amino acid product is produced in engineered E. coli and differs from the native human molecule in that it is non-glycosylated and contains an additional N-terminal methionine residue (a consequence of its prokaryotic expression system).

The purified product is presented as a solution and contains sodium citrate, EDTA, sodium chloride and polysorbate 80 as excipients. A daily (s.c.) injection of 100 mg is recommended for patients with rheumatoid arthritis. This inflammatory condition is (not surprisingly) characterized by the presence of high levels of IL-1 in the synovial fluid of affected joints. In addition to its pro-inflammatory properties, IL-1 also mediates additional negative influences on the joint/bone, including promoting cartilage degradation and stimulation of bone resorption.

An additional approach to IL-1 down-regulation could entail development of inhibitors of the proteolytic enzymes that release the active interleukin from its inactive precursor. Moreover, such inhibitors could probably be taken orally and, thus, would be suitable to treat chronic inflammation (the alternatives outlined above would be administered parenterally).

The enzyme that releases active IL-1P from its 31 kDa precursor has been identified and studied in detail. Termed IL-1P converting enzyme (ICE), it is a serine protease whose only known physiological substrate is the inactive IL-1P precursor. ICE cleaves this precursor between Asp 116 and Ala 117, releasing the active IL-1p.

ICE is an oligomeric enzyme (its active form may be a tetramer). It contains two distinct polypeptide subunits, p20 (20 kDa) and p10 (10 kDa). These two subunit types associate very closely, and the protease's active site spans residues from both. p10 and p20 are proteolytically derived from a single 45 kDa precursor protein.

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