A multicenter dose-escalation trial with denileukin diftitox (ONTAK, DAB389IL-2) in patients with severe psoriasis

Martin, Ann G.; Gutierrez, Elsa; Muglia, Jennie J.; McDonald, Charles J.; Guzzo, Cynthia; Gottlieb, Alice B.; Pappert, Amy; Garland, W. Thomas; Bagel, Jerry; Bacha, P.

doi:10.1067/mjd.2001.117852

Cited by 66 publications

(29 citation statements)

References 14 publications

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“…In doses usually reached in the patient's serum (10-100 ng/mL), 19 cell death of imDC increased by 10% to 25% but only by 2% to 5% in maDC (Figure 2A), indicating that imDC ingested DD despite a lack of IL-2R, including the IL-2R b-chain ( Figure 2D; supplemental Figure 2). In line with this assumption, blocking anti-CD25 antibodies (daclizumab) could not prevent DD-induced cell death of imDC (supplemental Figure 3).…”

Section: Dd Affects Dcs In Vivo and Alters Their Function In Vitromentioning

confidence: 99%

Denileukin diftitox (ONTAK) induces a tolerogenic phenotype in dendritic cells and stimulates survival of resting Treg

Baur

Lutz

Schierer

et al. 2013

Blood

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Section: Dd Affects Dcs In Vivo and Alters Their Function In Vitromentioning

confidence: 99%

Denileukin diftitox (ONTAK) induces a tolerogenic phenotype in dendritic cells and stimulates survival of resting Treg

Baur

Lutz

Schierer

et al. 2013

Blood

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“…Validation of this approach is evidenced by emerging clinical trial data with Ontak® (denileukin diftitox), a fusion protein combining IL-2 and diphtheria toxin. While this drug conjugate was originally approved by the FDA in 1999 for the treatment of cutaneous T cell lymphoma (CTCL), Ontak® has been evaluated in a variety of non-malignant disorders to ablate activated T lymphocytes with encouraging results (107,108). With the dramatic progress in linker, payload, and conjugation technologies since the original development of Ontak®, the potential remains to further improve the therapeutic window of ADCs for non-malignant disorders.…”

Section: Future Directionsmentioning

confidence: 99%

Antibody Drug Conjugates: Preclinical Considerations

Bornstein

2015

AAPS J

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ABSTRACT. The development path for antibody drug conjugates (ADCs) is more complex and challenging than for unmodified antibodies. While many of the preclinical considerations for both unmodified and antibody drug conjugates are shared, special considerations must be taken into account when developing an ADC. Unlike unmodified antibodies, an ADC must preferentially bind to tumor cells, internalize, and traffic to the appropriate intracellular compartment to release the payload. Parameters that can impact the pharmacological properties of this class of therapeutics include the selection of the payload, the type of linker, and the methodology for payload drug conjugation. Despite a plethora of in vitro assays and in vivo models to screen and evaluate ADCs, the challenge remains to develop improved preclinical tools that will be more predictive of clinical outcome. This review will focus on preclinical considerations for clinically validated small molecule ADCs. In addition, the lessons learned from Mylotarg®, the first in class FDA-approved ADC, are highlighted.

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“…The efficacy of alefacept [a fusion protein targeting leukocyte functioning antigen-3, LFA-3, which induces apoptosis of memory effector (activated) T cells in psoriasis] and efaluzimab (a monoclonal antibody to LFA-1), which also targets memory T cells in psoriasis, substantiate the view that T cells may have a primary pathogenic role [8,9] . In addition, the efficacy of the fusion protein DAB 389-IL-2 (comprising IL-2 and fragments of diphtheria toxin), which is selective for activated T lymphocytes in psoriasis, suggesting T cells are critical for psoriasis pathogenesis [10,11] . In contrast rituximab which targets B lymphocytes is not effective in treating the disease [12] .…”

Section: Current Therapies For Psoriasis Target T Lymphocytesmentioning

confidence: 99%

Natural Killer Cells in Psoriasis

Tobin¹,

Lynch

Kirby³

et al. 2011

J Innate Immun

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Psoriasis is one of the most common immune-mediated disorders. There is evidence that it is mediated by Th1 and, more recently, Th17 cells. The cytokine pattern, particularly the dominance of TNF-α, implicates the innate immune system in psoriasis pathogenesis. Of the many components of the innate immune system known to be involved in psoriatic lesions, natural killer and natural killer T cells appear to have a unique role. We review the evidence supporting a role for natural killer cells in psoriasis.

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A multicenter dose-escalation trial with denileukin diftitox (ONTAK, DAB389IL-2) in patients with severe psoriasis

Cited by 66 publications

References 14 publications

Denileukin diftitox (ONTAK) induces a tolerogenic phenotype in dendritic cells and stimulates survival of resting Treg

Denileukin diftitox (ONTAK) induces a tolerogenic phenotype in dendritic cells and stimulates survival of resting Treg

Antibody Drug Conjugates: Preclinical Considerations

Natural Killer Cells in Psoriasis

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