NNKTT120, an anti-iNKT cell monoclonal antibody, produces rapid and sustained iNKT cell depletion in adults with sickle cell disease

Joshua J. Field, Elaine Majerus, Kenneth Ataga, Elliot P. Vichinsky, Robert Schaub, Robert Mashal, David G. Nathan

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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 halflife 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.

Original languageEnglish (US)
Article number0171067
JournalPloS one
Volume12
Issue number2
DOIs
StatePublished - Feb 1 2017

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sickle cell anemia
Natural Killer T-Cells
Sickle Cell Anemia
monoclonal antibodies
Monoclonal Antibodies
dosage
Pharmacodynamics
cells
Pharmacokinetics
Toxicity
Labels
Blood
Tissue
Plasmas
pharmacology
NKTT120
Aptitude
pharmacokinetics
half life
pain

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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NNKTT120, an anti-iNKT cell monoclonal antibody, produces rapid and sustained iNKT cell depletion in adults with sickle cell disease. / Field, Joshua J.; Majerus, Elaine; Ataga, Kenneth; Vichinsky, Elliot P.; Schaub, Robert; Mashal, Robert; Nathan, David G.

In: PloS one, Vol. 12, No. 2, 0171067, 01.02.2017.

Research output: Contribution to journalArticle

Field, Joshua J. ; Majerus, Elaine ; Ataga, Kenneth ; Vichinsky, Elliot P. ; Schaub, Robert ; Mashal, Robert ; Nathan, David G. / NNKTT120, an anti-iNKT cell monoclonal antibody, produces rapid and sustained iNKT cell depletion in adults with sickle cell disease. In: PloS one. 2017 ; Vol. 12, No. 2.
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