DAB486IL-2 fusion toxin in refractory rheumatoid arthritis
| Autor: | Kathryn Lea Sewell, David E. Trentham, William G. Swartz, James M. Reuben, Thasia G. Woodworth, Karen C. Parker |
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| Rok vydání: | 1993 |
| Předmět: |
Adult
Male medicine.medical_specialty medicine.medical_treatment Recombinant Fusion Proteins Immunology Arthritis Gastroenterology Transaminase Immunophenotyping Arthritis Rheumatoid Rheumatology Fusion Toxin Internal medicine Immunology and Allergy Medicine Humans Pharmacology (medical) Diphtheria Toxin Lymphocytes Diphtheria toxin Chemotherapy Blood Cells Dose-Response Relationship Drug business.industry Therapeutic effect Receptors Interleukin-2 medicine.disease Solubility Rheumatoid arthritis Interleukin-2 Methotrexate Female business medicine.drug |
| Zdroj: | Arthritis and rheumatism. 36(9) |
| ISSN: | 0004-3591 |
| Popis: | Objective. To evaluate the safety and antiarthritic effects of DAB486IL-2. This agent is a fusion toxin and the product of a synthetic gene, engineered by replacing the codons for the receptor-binding domain of diphtheria toxin (DT) with the codons for human interleukin-2 (IL-2). DAB486IL-2 targets cells expressing the 2-chain, high-affinity form of the IL-2 receptor (IL-2R), and achieves selective diphtheria toxin–mediated cytotoxicity of activated T cells by inhibition of protein synthesis. Methods. Nineteen patients with rheumatoid arthritis (RA) that had been refractory to methotrexate participated in an open-label, phase I/II trial evaluating 3 dose levels of intravenous DAB486IL-2 given for 5 or 7 consecutive days. Thirteen patients received additional courses, at higher doses if the original response had been inadequate or at an equivalent dose if the original course produced a response, for a total of 38 courses. Arthritis response was assessed at 28 days, with biweekly followup of patients with substantial response (⩾50% improved) or meaningful response (⩾25% improved). Laboratory monitoring included measurement of CD4+ cells and circulating shed IL-2R. Results. Nine of 19 patients treated with high- or medium-dose DAB486IL-2 had a substantial or meaningful response after 1 or 2 treatment courses. No significant responses occurred with the low-dose regimen. Clinical benefit was rapid, with full effect noted by 14 days following completion of infusions. Antibodies to DT developed in all patients, or levels of preexisting antibodies were boosted. Adverse effects included transient elevation of transaminase levels (55% of the patients), fever (40%), nausea or anorexia (30%), hypersensitivity (6%), and thrombocytopenia (5%). Repeat courses were associated with less transaminase elevation and were clinically effective despite induction of anti-DT antibodies. Conclusion. The results of this open trial provide preliminary evidence for a potential therapeutic effect of DAB486IL-2 in RA, with an acceptable safety profile. Reversible transaminase elevations limit escalation of the dosage beyond 0.1 mg/kg/day. A controlled study of DAB486IL-2 is required to determine the efficacy of this high-affinity IL-2R–targeted fusion toxin in the treatment of RA. |
| Databáze: | OpenAIRE |
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