Product case study Ontak

Ontak (tradename, also known as denileukin diftitox) is an engineered fusion protein produced by recombinant means in E. coli. It gained approval for general medical use in the USA in 1999 and is indicated for the treatment of patients with cutaneous T-cell lymphoma (CTCL). The fusion product is composed of diphtheria toxin fragments A and B directly linked to IL-2. It displays a molecular weight of 58 kDa and is purified using reverse-phase chromatography and diafiltration. The product is formulated as a sterile frozen solution containing citric acid, EDTA and polysorbate as excipients. It is presented in single-use vials. The product is normally administered i.v. daily for five consecutive days every 3 weeks over the treatment period.

The IL-2 portion of the fusion protein facilitates product interaction with cells displaying cell surface IL-2 receptors, found in high levels on some leukaemia and lymphoma cells, including CTCL cells. Binding appears to trigger internalization of the receptor-fusion protein complex (Figure 9.B1). Sufficient quantities of the latter escape immediate cellular destruction to allow diphtheria toxin-mediated inhibition of cellular protein synthesis. Cell death usually results within hours.

Figure 9.B1 Mechanism of Ontak action

Pharmacokinetic studies indicate the product displays two-compartment behaviour, with a distribution phase (half-life 2-5 min) and a terminal phase (half-life 70-80 min). Development of antibodies to the product significantly impacts upon clearance rates.

The major clinical study underpinning product approval was a randomized, double blind study in which 71 CTCL patients were administered the product at one of two dosage levels (9 or 18 |g kg-1 day-1); overall, 30 per cent of patients experienced an objective tumour response. Serious side effects potentially associated with product administration include acute hypersen-sitivity-type reactions, vascular leak syndrome and visual impairment. Additional adverse reactions include flu-like symptoms, headache, hyper- or hypo-tension, as well as digestive upset. Ontak is manufactured by Seragen Inc. and is distributed by Ligand Pharmaceuticals.

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