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 I Ataga,Robert Mashal,Robert Schaub,David G Nathan,Elliot P Vichinsky

doi:10.1371/journal.pone.0171067

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 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.

Highlights

Vaso-occlusion (VO) of post-capillary venules is the predominant cause of morbidity and mortality for patients with sickle cell disease (SCD) [1]
Another potential mechanism of Invariant NKT (iNKT) cell activation in SCD is through interactions between secretory phospholipase A2, a lipid elevated in the plasma of patients with SCD, and phosphotidylserine (PS), a lipid abnormally exposed on the outer membrane of sickle erythrocytes [7]
At higher doses (0.1, 0.3, 1 mg/kg), all subjects were depleted of iNKT cells within 6 hours, but the length of time they remained depleted varied between subjects

Summary

Introduction

Vaso-occlusion (VO) of post-capillary venules is the predominant cause of morbidity and mortality for patients with sickle cell disease (SCD) [1]. One mechanism is thought to involve danger-associated molecular patterns (DAMPs), which may be generated during VO and can activate toll-like receptors on APCs to synthesize and present glycolipids to iNKT cells [6] Another potential mechanism of iNKT cell activation in SCD is through interactions between secretory phospholipase A2 (sPLA2), a lipid elevated in the plasma of patients with SCD, and phosphotidylserine (PS), a lipid abnormally exposed on the outer membrane of sickle erythrocytes [7]. Regardless of the mechanism, once activated, iNKT cells promptly secrete cytokines (interferon-gamma (IFN-γ), interleukin-4 (IL-4) and others) that can activate downstream effector cells and vascular endothelium as well as proteolytic enzymes, such as perforin and granzymes, which can produce tissue injury [12] This rapid, non-specific activation, akin to the activation of innate immune cells, enables iNKT cells to instigate and sustain a broad inflammatory response that is characteristic of SCD and critical to pathogenesis of VO

Objectives

Methods

Results

Conclusion