NNKTT120, an anti-iNKT cell monoclonal antibody, produces rapid and sustained iNKT cell depletion in adults with sickle cell disease
| Autor: | Kenneth I. Ataga, Robert Mashal, Robert Schaub, David G. Nathan, Elaine M. Majerus, Joshua J. Field, E. Vichinsky |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Physiology lcsh:Medicine Cohort Studies White Blood Cells 0302 clinical medicine Animal Cells Immune Physiology Medicine and Health Sciences Child lcsh:Science Innate Immune System Multidisciplinary Hematology T Cells Natural killer T cell Body Fluids Blood Research Design Genetic Diseases 030220 oncology & carcinogenesis Toxicity Monoclonal Cytokines Female Antibody Cellular Types Anatomy Research Article Half-Life Adult medicine.medical_specialty Adolescent Clinical Research Design Immune Cells Immunology Anemia Sickle Cell Biology Research and Analysis Methods Antibodies Monoclonal Humanized Lymphocyte Depletion 03 medical and health sciences Young Adult Immune system Pharmacokinetics Autosomal Recessive Diseases Internal medicine medicine Animals Humans Pharmacology Clinical Genetics Sickle Cell Disease Blood Cells lcsh:R Biology and Life Sciences Cell Biology Molecular Development Health Care Hemoglobinopathies 030104 developmental biology Pharmacodynamics Immune System biology.protein Natural Killer T-Cells lcsh:Q Adverse Events Health Statistics Morbidity Developmental Biology |
| Zdroj: | PLoS ONE, Vol 12, Iss 2, p e0171067 (2017) PLoS ONE |
| DOI: | 10.17615/vfrm-mn40 |
| Popis: | Invariant NKT (iNKT) cells can be activated to stimulate a broad inflammatory response. In murine models of sickle cell disease (SCD), interruption of iNKT cell activity prevents tissue injury from vaso-occlusion. NKTT120 is an anti-iNKT cell monoclonal antibody that has the potential to rapidly and specifically deplete iNKT cells and, potentially, prevent vaso-occlusion. We conducted an open-label, multi-center, single-ascending-dose study of NKTT120 to determine its pharmacokinetics, pharmacodynamics and safety in steady-state patients with SCD. Doses were escalated in a 3+3 study design over a range from 0.001 mg/kg to 1.0 mg/kg. Twenty-one adults with SCD were administered NKTT120 as part of 7 dose cohorts. Plasma levels of NKTT120 predictably increased with higher doses. Median half-life of NKTT120 was 263 hours. All subjects in the higher dose cohorts (0.1 mg/kg, 0.3 mg/kg, and 1 mg/kg) demonstrated decreased iNKT cells below the lower limit of quantification within 6 hours after infusion, the earliest time point at which they were measured. In those subjects who received the two highest doses of NKTT120 (0.3, 1 mg/kg), iNKT cells were not detectable in the peripheral blood for a range of 2 to 5 months. There were no serious adverse events in the study deemed to be related to NKTT120. In adults with SCD, NKTT120 produced rapid, specific and sustained iNKT cell depletion without any infusional toxicity or attributed serious adverse events. The next step is a trial to determine NKTT120’s ability to decrease rate of vaso-occlusive pain episodes. Trial Registration: clinicaltrials.gov NCT01783691. |
| Databáze: | OpenAIRE |
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