Drug Development

Misfolded protein deposits illicit a cascade of autoreactive T-cell mediated neuroinflammation and damage in Alzheimer's disease (AD). These T cells have high CXCR3 expression enabling them to cross the BBB. Natural Killer (NK) cells are a key component of the innate immune system that have shown potential to slow amyloid deposition and eliminate autoreactive T-cells and damaged neurons via NKG2D and DNAM-1 expression. Troculeucel is a first-in-kind, autologous non-genetically modified NK cell product with significant increased cytotoxicity and over 90% activating receptor expression that can be consistently produced from any donor.

In vitro studies were performed to evaluate whether Troculeucel could identify and eliminate amyloid and alpha-synuclein proteins, as well as auto-reactive T cells. Additionally, Troculeucel was administered to 13 patients in two Phase I trials (NCT04678453 and NCT06189963). The primary endpoint was safety while secondary endpoints included changes in cognitive assessment and CSF/plasma biomarkers. Troculeucel was also characterized for CXCR3 expression and other activating receptors required to help NK cells identify auto-reactive T cells.

In vitro studies comparing Troculeucel to microglia (HMC3 cells) found Troculeucel could phagocytose and digest amyloid and alpha-synuclein proteins similar to microglia. Troculeucel exhibited 99% DNAM-1 and NKG2D expression and was only activated in the presence of autoreactive T-cells while leaving resting T cells alone. Troculeucel was also found to have high CXCR3 expression (91.25%). Combined Phase I data revealed that 12/13 (92.3%) patients had stable or improved ADCOMS scores at three months (Week 11 for NCT04678453 and Week 14 for NCT06189963). Troculeucel crossed the BBB after simple IV administration, leading to dose-dependent improvement in CSF levels of AB 42/40, p-tau, and alpha-synuclein. Notably, 9/13 (69.23%) of patients showed significant improvement in CSF levels of GFAP at three months including 100% at the highest dose level of 6 x 10⁹ cells per infusion.

Troculeucel is consistently produced from AD patients and can cross the blood-brain barrier via CXCR3 to improve CSF levels of amyloid and alpha-synuclein proteins, while targeting autoreactive T cells to reduce neuroinflammation. Reduction of GFAP appears to be correlated with stabilization or improvement in ADCOMS scores observed in the study.