P11.36.A BARRIER DISRUPTING FIELDS, INDUCING BLOOD-ARACHNOID BARRIER DISRUPTION, ENABLE NON-INVASIVE/EFFICIENT DELIVERY OF ANTIBODIES INTO THE CSF FOR THE TREATMENT OF LEPTOMENINGEAL DISEASE

Abstract BACKGROUND Leptomeningeal diseases remain exceptionally challenging to treat, primarily due to poor drug penetration across the blood-CSF-barrier, specifically the blood-arachnoid barrier (BAB). We previously demonstrated that barrier disrupting fields (BDF), based on pulsed electric fields (PEFs), can be applied non-invasively to induce blood-brain barrier opening and enable efficient drug delivery into mice brains. Here we demonstrate BDF application for transient BAB opening (BABo) in rats leading to a FIH study. MATERIAL AND METHODS An in silico model of electric fields distribution in the rat brain was constructed using MRI data, enabling the assessment of BABo levels as a function of exposure to PEFs. The model predicted CSF antibody concentrations based on brain MRI, serum concentration and BDF treatment parameters. To validate the simulation electrodes were attached to the heads of rats and increasing voltages were applied while measuring resulting currents. Voltage-current plots were then compared to the simulation predictions. Subsequently, Nivolumab or Trastuzumab was administered IV before BDF, and CSF samples were collected before and periodically after BDF (15 min to 4 hours post treatment). Various BDF protocols were tested (100-200 50 µs pulses, 0-700 V, 4 Hz, 25-60 sec total). CSF antibody concentrations were used to calculate the amount of drug crossing the BAB per mm2 as a function of local PEFs exposure. These findings were than translated into a human in silico model to plan personalized BDF treatments - including electrode configuration and PEFs parameters - based on individual brain MRI data, for the FIH study. RESULTS The voltage-current plots demonstrated a strong linear correlation (r2>0.99) between predicted and measured currents, validating the simulation’s accuracy. The threshold for BABo was determined to be 20 V/cm, consistent with our prior in vitro results. BABo was found to increase linearly with the number of pulses and exponentially with the pulse amplitudes. CSF analysis confirmed significant penetration of both antibodies under all tested conditions, with peak CSF concentrations in the range of 150 ng/ml in the rats CSF following BDF. These results supported the initiation of a FIH study combining BDF with monoclonal antibody therapy for the treatment of leptomeningeal diseases. CONCLUSION This study demonstrates the feasibility of achieving therapeutic antibody concentrations in the CSF through transient and safe BABo using short duration (minutes) non-invasive BDF treatment in rats. These findings lay the groundwork for a novel and efficient treatment modality for leptomeningeal diseases. SUPPORT Grants from the Israel Cancer Research Fund, Israel Science Foundation and Israeli Ministry of Sciences.