Clinical applications

The majority of clinical experience using diphtheria-based fusion protein toxin constructs has been with the IL-2 receptor targeting constructs. The specific expression of the high affinity IL-2 receptor on only activated and proliferating T cells makes DAB389IL-2 a potential therapeutic for the treatment of both T-cell mediated malignancies and autoimmune diseases. The progression of disease in both states often results in the emergence of resistance to chemotherapy and subsequent treatment failure, and highlights the need for the development of new therapeutic agents.

In the context of malignant disease, IL-2 receptor expression is reported in various subsets of hematopoeitic malignancies of T-cell origin, such as cutaneous T-cell lymphoma (CTCL), low and intermediate grade non-Hodgkin's lymphoma, HTLV-1 associated adult T-cell leukemia/lymphoma, and chronic lymphocytic leukemia (Foss et al., 1998). Signaling pathways mediated by the IL-2 receptor are a requirement for T-cell activation and proliferation, and IL-2 receptor expression is frequently upregulated in the neoplasms of T-cell origin. Expression of the high affinity IL-2 receptor is also an obligatory event in the development of T-cell mediated immune response, and upregulation of the receptor on auto-aggressive T cells marks an early common event in the pathogenesis of essentially all autoimmune diseases (Murphy and vanderSpek, 2000). The potency and selectivity of the IL-2 targeted diphtheria-based fusion protein toxin offers significant advantages over conventional therapeutics, such as a reduction in the occurrence of adverse effects.

The development of diphtheria-based fusion protein toxins for the treatment of malignant disease is not limited to the IL-2 targeted constructs, and the number of novel constructs being reported in the literature is increasing. While many of the clinical observations made using DAB389IL-2 will hold true for other diphtheria-based fusion protein toxins, clinical trials are needed to evaluate the safety, efficacy, and pharmacokinetics of each novel fusion protein toxin construct. Furthermore, the safety, efficacy, and pharmacokinetics of any diphtheria-based fusion protein toxin must be evaluated in the context of each and every disease state to which it is applied.

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