Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
ADULT T-CELL LEUKEMIA: PROSPECTS FOR IMMUNOTHERAPY
The Human Retroviruses. Gallo RC and Jay G, eds. San Diego, Academic Press, p. 319-32, 1991.. Unique Identifier : AIDSLINE ICDB/92678733 Waldmann TA; Metabolism Branch, NCI, Bethesda, MD 20892
Abstract:
Immune intervention is playing an increasing role in therapy, but the potential provided by the great specificity of the human immune system clearly has not been achieved. Interleukin-2 receptor (IL-2R) has been employed as a target for immune intervention in patients with adult T-cell leukemia (ATL). The prospects for this approach to immunotherapy are reviewed, including structure and function of the multisubunit IL-2R; disorders of IL-2R expression in malignant and autoimmune diseases; and disorders of IL-2R expression in human T-cell leukemia virus-I (HTLV-I)-associated ATL. A multichain model has been proposed for the high-affinity IL-2R that involves two IL-2-binding peptides: a 70/75-kD beta- and a 55-kD alpha-peptide, which are associated in a receptor complex. A series of additional peptides of Mr 22,000, 35,000, 40,000, 75,000 (non-IL-2 binding), 95,000-105,000, and 180,000 have been associated with the IL-2-binding peptides. In contrast to resting T cells, the abnormal T cells of patients with certain autoimmune disorders, individual rejecting allografts, and patients with HTLV-I-associated tropical spastic paraparesis or ATL express the Tac peptide of the IL-2R. To exploit this difference in Tac expression, therapeutic trials were initiated using unmodified anti-Tac, anti-Tac variable region truncated toxin fusion proteins [anti-Tac(Fv)-PE40], IL-2 mutated toxin fusion proteins (IL-PE66(4)-Glu) and alpha- and beta-emitting isotopic chelates of anti-Tac. Humanized hyperchimeric anti-Tac molecules (anti-Tac-H) have been prepared by genetic engineering in which the molecule is entirely human IgG1 except for the small complementarity-determining regions that are retained by the mouse antibody. The IgG1 hyperchimerics manifested a new activity of antibody-dependent cell-mediated cytotoxicity with human mononuclear cells that was absent in the parental mouse anti-Tac. Thus, the present understanding of the IL-2/IL-2R system opens the possibility for more specific immune intervention strategies. The IL-2R may prove to be an extraordinarily versatile therapeutic target. (63 Refs)
Keywords: Antibodies, Monoclonal/ADMINISTRATION & DOSAGE/IMMUNOLOGY Gene Expression Regulation, Viral/*PHYSIOLOGY Human HTLV-I/GENETICS/*IMMUNOLOGY Immunotherapy/*METHODS Leukemia-Lymphoma, T-Cell, Acute, HTLV-I-Associated/GENETICS/ IMMUNOLOGY/*THERAPY Receptors, Interleukin-2/GENETICS/*IMMUNOLOGY Recombinant Proteins/ADMINISTRATION & DOSAGE MONOGRAPH REVIEW
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Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
