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Journal of Immunology (Baltimore, Md. :... Aug 2012Denileukin diftitox, also known as DAB(389)IL-2 or Ontak, is a fusion protein toxin consisting of the full-length sequence of the IL-2 protein and as toxophore the...
The IL-2 diphtheria toxin fusion protein denileukin diftitox modulates the onset of diabetes in female nonobese diabetic animals in a time-dependent manner and breaks tolerance in male nonobese diabetic animals.
Denileukin diftitox, also known as DAB(389)IL-2 or Ontak, is a fusion protein toxin consisting of the full-length sequence of the IL-2 protein and as toxophore the truncated diphtheria toxin. As a consequence, it delivers the toxic agent to CD25-bearing cells, whereby CD25 represents the high-affinity α-subunit of the IL-2 receptor. Initially it was developed for the treatment of patients with cutaneous T cell lymphoma. Meanwhile, denileukin diftitox is also used as an adjuvant in other tumor therapies and neoplastic disorders. In this study, to our knowledge we report for the first time that denileukin diftitox has also dramatic effects regarding the pathology of type 1 diabetes using the NOD mouse model. Repeated injections of denileukin diftitox into female NOD mice at 12 wk of age led to a clear acceleration of disease onset, whereas injection at 7 wk of age did not. Using male NOD mice, which are much less susceptible to diabetes, we demonstrate that the injection of denileukin diftitox leads to a dramatic development of type 1 diabetes within days after injection, thereby obviously breaking pre-existing tolerance mechanisms. This is accompanied by an increased IFN-γ production of autoreactive splenic cells and a decreased presence of regulatory CD4(+)CD25(+)Foxp3(+) T cells. In contrast, transfer of CD4(+)CD25(+)Foxp3(+) T cells could correct the defect after denileukin diftitox treatment. Furthermore, whereas IFN-γ production was increased in the pancreata of treated animals, insulin expression was strongly reduced. These finding should be considered when denileukin diftitox is used for the treatment of patients suffering from tumors and/or autoimmune disorders.
Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diphtheria Toxin; Disease Progression; Female; Immune Tolerance; Interleukin-2; Male; Mice; Mice, Inbred NOD; Mice, SCID; Prediabetic State; Recombinant Fusion Proteins; Time Factors
PubMed: 22730534
DOI: 10.4049/jimmunol.1102691 -
Journal of Clinical Oncology : Official... Jan 2001The objective of this phase III study was to determine the efficacy, safety, and pharmacokinetics of denileukin diftitox (DAB389IL-2, Ontak [Ligand Pharmaceuticals Inc,... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
PURPOSE
The objective of this phase III study was to determine the efficacy, safety, and pharmacokinetics of denileukin diftitox (DAB389IL-2, Ontak [Ligand Pharmaceuticals Inc, San Diego, CA]) in patients with stage Ib to IVa cutaneous T-cell lymphoma (CTCL) who have previously received other therapeutic interventions.
PATIENTS AND METHODS
Patients with biopsy-proven CTCL that expressed CD25 on > or = 20% of lymphocytes were assigned to one of two dose levels (9 or 18 microg/kg/d) of denileukin diftitox administered 5 consecutive days every 3 weeks for up to 8 cycles. Patients were monitored for toxicity and clinical efficacy, the latter assessed by changes in disease burden and quality of life measurements. Antibody levels of antidenileukin diftitox and anti-interleukin-2 and serum concentrations of denileukin diftitox were also measured.
RESULTS
Overall, 30% of the 71 patients with CTCL treated with denileukin diftitox had an objective response (20% partial response; 10% complete response). The response rate and duration of response based on the time of the first dose of study drug for all responders (median of 6.9 months with a range of 2.7 to more than 46.1 months) were not statistically different between the two doses. Adverse events consisted of flu-like symptoms (fever/chills, nausea/vomiting, and myalgias/arthralgias), acute infusion-related events (hypotension, dyspnea, chest pain, and back pain), and a vascular leak syndrome (hypotension, hypoalbuminemia, edema). In addition, 61% of the patients experienced transient elevations of hepatic transaminase levels with 17% grade 3 or 4. Hypoalbuminemia occurred in 79%, including 15% with grade 3 or 4 changes. Tolerability at 9 and 18 microg/kg/d was similar, and there was no evidence of cumulative toxicity.
CONCLUSION
Denileukin diftitox has been shown to be a useful and important agent in the treatment of patients whose CTCL is persistent or recurrent despite other therapeutic interventions.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Diphtheria Toxin; Drug Administration Schedule; Female; Humans; Immunohistochemistry; Interleukin-2; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Neoplasm Staging; Proteins; Receptors, Interleukin-2; Recombinant Fusion Proteins; Remission Induction
PubMed: 11208829
DOI: 10.1200/JCO.2001.19.2.376 -
Expert Opinion on Emerging Drugs Sep 2017Antibody-drug conjugates (ADC) are monoclonal antibodies (Mabs) attached to biologically active drugs through specialized chemical linkers. They deliver and release... (Review)
Review
Antibody-drug conjugates (ADC) are monoclonal antibodies (Mabs) attached to biologically active drugs through specialized chemical linkers. They deliver and release cytotoxic agents at the tumor site, reducing the likelihood of systemic exposure and therefore toxicity. These agents should improve the potency of chemotherapy by increasing the accumulation of cytotoxic the drug within or near the neoplastic cells with reduced systemic effects. Areas covered: A literature review was conducted of the MEDLINE database PubMed for articles in English examining Mabs, B-cell receptor pathway inhibitors and immunomodulating drugs. Publications from 2000 through April 2017 were scrutinized. Conference proceedings from the previous five years of the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, and ACR/ARHP Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles. Expert opinion: Newer ADCs show promise as treatment for several hematologic malignancies, especially lymphoma, multiple myeloma, and leukemia. However, definitive data from ongoing and future clinical trials will aid in better defining the status of these agents in the treatment of these diseases.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Drug Delivery Systems; Humans; Immunoconjugates; Leukemia; Lymphoma; Multiple Myeloma
PubMed: 28792782
DOI: 10.1080/14728214.2017.1366447 -
Blood Aug 2004Denileukin diftitox (Ontak), a recombinant protein composed of human interleukin 2 (IL-2) fused to diphtheria toxin, has selective cytotoxicity against activated... (Clinical Trial)
Clinical Trial
Denileukin diftitox (Ontak), a recombinant protein composed of human interleukin 2 (IL-2) fused to diphtheria toxin, has selective cytotoxicity against activated lymphocytes expressing the high-affinity IL-2 receptor. We conducted a phase 1 study of denileukin diftitox in 30 patients with steroid refractory acute graft-versus-host disease (GVHD). Seven patients received 9 microg/kg intravenously on days 1 and 15; 18 received 9 microg/kg intravenously on days 1, 3, 5, 15, 17, and 19; and 5 received 9 microg/kg intravenously on days 1 to 5 and 15 to 19. Hepatic transaminase elevation was the dose-limiting toxicity (DLT), and dose level 2 was the maximum tolerated dose (MTD). Overall, 71% of patients responded with complete resolution (12 of 24; 50%) or partial resolution (5 of 24; 21%) of GVHD. Eight of 24 patients (33%) are alive at 6.3 to 24.6 months (median, 7.2 months). Denileukin diftitox is tolerable and has promising activity in steroid-refractory acute GVHD.
Topics: Acute Disease; Adult; Aged; Diphtheria Toxin; Dose-Response Relationship, Drug; Drug Resistance; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Interleukin-2; Lymphocyte Activation; Lymphocyte Depletion; Male; Middle Aged; Recombinant Fusion Proteins; Salvage Therapy; Steroids; T-Lymphocytes; Transplantation, Homologous; Treatment Outcome
PubMed: 15113758
DOI: 10.1182/blood-2004-01-0028 -
Journal of the American Academy of... Dec 2001Denileukin diftitox, a fusion protein targeting both malignant and normal activated lymphocytes, has been shown previously to have antipsoriatic activity. However, the... (Clinical Trial)
Clinical Trial
BACKGROUND
Denileukin diftitox, a fusion protein targeting both malignant and normal activated lymphocytes, has been shown previously to have antipsoriatic activity. However, the ideal dosing regimen for treating psoriasis was not established.
OBJECTIVE
We examined the safety and efficacy of denileukin diftitox in patients with severe plaque-type psoriasis.
METHODS
This was a cohort dose-escalation trial. Patients were administered denileukin diftitox on 3 consecutive days every other week. Patients were evaluated for toxicity, improvement in psoriasis, immunogenicity, and serum levels.
RESULTS
Thirty-five patients were treated at 3 dose levels. Eight patients had a 50% decrease or more in Psoriasis Area and Severity Index score from baseline (0/10 at 0.5 microg/kg per day, 1/10 at 1.5 microg/kg per day, and 7/15 at 5 microg/kg per day). Adverse events primarily consisted of constitutional events and skin reactions.
CONCLUSIONS
The potential antipsoriatic activity of denileukin diftitox demonstrated in this study was comparable to that observed in other psoriasis studies with this agent. However, this dosing regimen was better tolerated than the dosing regimen used in the last study with denileukin diftitox in psoriasis patients.
Topics: Adult; Aged; Aged, 80 and over; Diphtheria Toxin; Drug Administration Schedule; Female; Humans; Interleukin-2; Male; Middle Aged; Multicenter Studies as Topic; Proteins; Psoriasis; Recombinant Fusion Proteins; Safety
PubMed: 11712032
DOI: 10.1067/mjd.2001.117852 -
The Journal of Investigative Dermatology Mar 2006Denileukin diftitox (Ontak), a recombinant fusion protein of diphtheria toxin and ligand, IL-2, binds to the IL-2 receptor, is internalized, and causes cell death....
Denileukin diftitox (Ontak), a recombinant fusion protein of diphtheria toxin and ligand, IL-2, binds to the IL-2 receptor, is internalized, and causes cell death. Denileukin diftitox was approved for the treatment of cutaneous T-cell lymphomas (CTCLs) with CD25+ expression. We prospectively stained lesional skin biopsy specimens from 113 mycosis fungoides and Sézary Syndrome patients for activation markers CD25 and CD30 to correlate expression with clinical tumor-node metastasis (TNM) stage, histologic grade, and response to denileukin diftitox. High expression was defined as positivity of > or =20% of lesional T-cells using immunohistochemistry (IHC). CD25 and CD30 expression was more common in lesions from advanced patients (P = 0.04 and 0.002, respectively). Advanced TNM (T3 or T4) was significantly associated with intermediate-grade (P = 0.002) and large-cell transformation histology (P = 0.04). Of interest, clinical responses were observed in 78.5% of patients with high CD25 expression versus 20% with low to undetectable CD25 expression (P = 0.01) among 24 patients receiving standard 5-day infusions of denileukin diftitox at 18 microg/kg/day. These data suggest that high CD25 expression by IHC is associated with advanced CTCL and with clinical response to denileukin diftitox therapy.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bexarotene; Diphtheria Toxin; Female; Humans; Interleukin-2; Ki-1 Antigen; L-Lactate Dehydrogenase; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Receptors, Interleukin-2; Recombinant Fusion Proteins; Skin; Skin Neoplasms; Tetrahydronaphthalenes
PubMed: 16410787
DOI: 10.1038/sj.jid.5700122 -
Clinical Lymphoma Mar 2002Cutaneous T-cell lymphoma (CTCL) can be associated with painful, pruritic, disfiguring lesions. As part of a multicenter, randomized phase III trial in patients with... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Cutaneous T-cell lymphoma (CTCL) can be associated with painful, pruritic, disfiguring lesions. As part of a multicenter, randomized phase III trial in patients with heavily pretreated advanced and/or recurrent CTCL, the effects of an interleukin-2 receptor-targeted fusion protein, denileukin diftitox (DAB389IL-2, ONTAK), on patient-rated overall quality of life (QOL), skin appearance, and pruritus severity were evaluated. A total of 71 patients with stage IB-IVA CTCL received intravenous denileukin diftitox 9 microg/kg/day or 18 microg/kg/day over 15-60 minutes for 5 consecutive days on an outpatient basis; cycles were planned for every 21 days for a total of 8 cycles over 6 months. Prior to each treatment cycle, patients were evaluated for disease response and were asked to self-rate their overall QOL via the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire, skin appearance (7-point scale), and pruritus severity (10-cm visual analogue scale). Composite FACT-G and most individual subscale scores (physical, social/family, emotional, and functional well being) in documented responders (n = 21) gradually increased during the study period, generally reaching statistical significance (P < 0.05) by cycle 3, and were significantly (P < or = 0.041) higher than the scores of nonresponders at endpoint. Additionally for responders, assessments of skin severity and pruritus severity showed significant (P < or = 0.05) improvements at study endpoint compared with baseline. Adverse transfusion-related events (eg, hypersensitivity reactions, flu-like syndrome) were common during cycles 1 and 2, and vascular-leak syndrome occurred in 25% of patients. Denileukin diftitox was not associated with any clinically significant myelosuppression. Heavily pretreated patients with advanced and/or recurrent CTCL who responded to denileukin diftitox therapy showed significant improvements in self-rated overall QOL, skin appearance, and pruritus severity.
Topics: Adult; Aged; Antineoplastic Agents; Diphtheria Toxin; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Interleukin-2; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Neoplasm Staging; Patient Satisfaction; Probability; Prognosis; Prospective Studies; Quality of Life; Recombinant Fusion Proteins; Reference Values; Risk Assessment; Skin Neoplasms; Statistics, Nonparametric; Treatment Outcome
PubMed: 11970761
DOI: 10.3816/clm.2002.n.003 -
Seminars in Oncology Feb 2006Rexinoids have shown clinical activity in hematologic malignancies by mediating genes associated with both growth and differentiation. Consequently, these compounds are... (Review)
Review
Rexinoids have shown clinical activity in hematologic malignancies by mediating genes associated with both growth and differentiation. Consequently, these compounds are increasingly being investigated for the treatment of cutaneous T-cell lymphomas. Combining rexinoids with interleukin-2 receptor-targeted therapies, such as denileukin diftitox, would appear to be a rational therapy option in the treatment of lymphoid malignancies. This article discusses the use of rexinoids in combination with these pharmacotherapeutic agents, together with their use in combination with extracorporeal photophoresis and explores practical clinical approaches that may help to evoke immunomodulatory effects in targeted tumor cells, and ultimately lead to improved clinical outcome.
Topics: Antineoplastic Agents; Diphtheria Toxin; Humans; Immunologic Factors; Interleukin-2; Lymphoma, T-Cell, Cutaneous; Receptors, Interleukin-2; Recombinant Fusion Proteins; Retinoid X Receptors; Retinoids; Skin Neoplasms
PubMed: 16516672
DOI: 10.1053/j.seminoncol.2005.12.019 -
Blood Jul 2005Denileukin diftitox, a genetically engineered fusion protein combining the enzymatically active domains of diphtheria toxin and the full-length sequence for... (Clinical Trial)
Clinical Trial
Denileukin diftitox, a genetically engineered fusion protein combining the enzymatically active domains of diphtheria toxin and the full-length sequence for interleukin-2 (IL-2), efficiently targets lymphoma cells expressing the high-affinity IL-2 receptor (IL-2R) consisting of the alpha/p55/CD25, beta/p75/CD122, and gamma/p64/CD132 chains. In vitro studies demonstrated that the retinoid X receptor (RXR) retinoid, bexarotene, at biologically relevant concentrations of 10(-6) M to 10(-8) M, upregulated both the p55 and p75 subunits of the IL-2R and enhanced 5- to 10-fold the susceptibility of T-cell leukemia cells to denileukin diftitox. To determine whether this biomodulatory effect could be recapitulated in vivo, we treated 14 patients with relapsed or refractory cutaneous T-cell lymphoma with escalating doses of bexarotene (75 mg/day-300 mg/day) and denileukin diftitox (18 mcg/kg per day x 3 days every 21 days) in a phase 1 trial. Overall response was 67% (4 complete responses, 4 partial responses). Modulation of IL-2R expression was observed at or above a bexarotene dose of 150 mg/day. Four patients experienced grade 2 or 3 leukopenia, and 2 had grade 4 lymphopenia. Our results demonstrate that the combination of denileukin diftitox and bexarotene is well tolerated and that even low doses (150 mg/day) of bexarotene are capable of in vivo upregulation of CD25 expression on circulating leukemia cells.
Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bexarotene; Diphtheria Toxin; Drug Tolerance; Female; Humans; Interleukin-2; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Receptors, Interleukin-2; Recombinant Fusion Proteins; Recurrence; Skin Neoplasms; Tetrahydronaphthalenes; Up-Regulation
PubMed: 15811959
DOI: 10.1182/blood-2004-11-4570 -
Journal of the National Cancer Institute Nov 2011Unlike cytotoxic agents that indiscriminately affect rapidly dividing cells, newer antineoplastic agents such as targeted therapies and immunotherapies are associated... (Review)
Review
Unlike cytotoxic agents that indiscriminately affect rapidly dividing cells, newer antineoplastic agents such as targeted therapies and immunotherapies are associated with thyroid dysfunction. These include tyrosine kinase inhibitors, bexarotene, radioiodine-based cancer therapies, denileukin diftitox, alemtuzumab, interferon-α, interleukin-2, ipilimumab, tremelimumab, thalidomide, and lenalidomide. Primary hypothyroidism is the most common side effect, although thyrotoxicosis and effects on thyroid-stimulating hormone secretion and thyroid hormone metabolism have also been described. Most agents cause thyroid dysfunction in 20%-50% of patients, although some have even higher rates. Despite this, physicians may overlook drug-induced thyroid dysfunction because of the complexity of the clinical picture in the cancer patient. Symptoms of hypothyroidism, such as fatigue, weakness, depression, memory loss, cold intolerance, and cardiovascular effects, may be incorrectly attributed to the primary disease or to the antineoplastic agent. Underdiagnosis of thyroid dysfunction can have important consequences for cancer patient management. At a minimum, the symptoms will adversely affect the patient's quality of life. Alternatively, such symptoms can lead to dose reductions of potentially life-saving therapies. Hypothyroidism can also alter the kinetics and clearance of medications, which may lead to undesirable side effects. Thyrotoxicosis can be mistaken for sepsis or a nonendocrinologic drug side effect. In some patients, thyroid disease may indicate a higher likelihood of tumor response to the agent. Both hypothyroidism and thyrotoxicosis are easily diagnosed with inexpensive and specific tests. In many patients, particularly those with hypothyroidism, the treatment is straightforward. We therefore recommend routine testing for thyroid abnormalities in patients receiving these antineoplastic agents.
Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Anticarcinogenic Agents; Antineoplastic Agents; Bexarotene; Diphtheria Toxin; Humans; Hyperthyroidism; Hypopituitarism; Hypothyroidism; Interferon-alpha; Interleukin-2; Iodine Radioisotopes; Ipilimumab; Lenalidomide; Molecular Targeted Therapy; Neoplasms; Protein-Tyrosine Kinases; Quality of Life; Radioimmunotherapy; Recombinant Fusion Proteins; Recombinant Proteins; Tetrahydronaphthalenes; Thalidomide; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Thyroiditis, Autoimmune
PubMed: 22010182
DOI: 10.1093/jnci/djr373