Advancing Hyperspectral Targeted Alpha Therapy with Adversarial Machine Learning.

Targeted Alpha Therapy (TAT) has emerged as a promising modality for the treatment of various malignancies, leveraging the high linear energy transfer (LET) and short range of alpha particles to selectively irradiate cancer cells while sparing healthy tissue. Monitoring and optimizing TAT delivery is crucial for its clinical success. Hyper-spectral Single Photon Imaging (HSPI) presents a novel and versatile approach for the real-time assessment of TAT in vivo. This study introduces a comprehensive framework for HSPI in TAT, encompassing spectral unmixing, quantitative dosimetry, and spatiotemporal visualization. We report the development of a dedicated HSPI system tailored to alpha-emitting radionuclides, enabling the simultaneous acquisition of high-resolution spectral data and single-photon localization. Utilizing advanced spectral unmixing algorithms, we demonstrate the discrimination of alpha-induced scintillation from background fluorescence, facilitating precise alpha particle tracking with adversarial machine learning.

Deep optoacoustic localization microangiography of ischemic stroke in mice.

Super-resolution optoacoustic imaging of microvascular structures deep in mammalian tissues has so far been impeded by strong absorption from densely-packed red blood cells. Here we devised 5 µm biocompatible dichloromethane-based microdroplets exhibiting several orders of magnitude higher optical absorption than red blood cells at near-infrared wavelengths, thus enabling single-particle detection in vivo. We demonstrate non-invasive three-dimensional microangiography of the mouse brain beyond the acoustic diffraction limit (<20 µm resolution). Blood flow velocity quantification in microvascular networks and light fluence mapping was also accomplished. In mice affected by acute ischemic stroke, the multi-parametric multi-scale observations enabled by super-resolution and spectroscopic optoacoustic imaging revealed significant differences in microvascular density, flow and oxygen saturation in ipsi- and contra-lateral brain hemispheres. Given the sensitivity of optoacoustics to functional, metabolic and molecular events in living tissues, the new approach paves the way for non-invasive microscopic observations with unrivaled resolution, contrast and speed.

Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033.

OBJECTIVE: To evaluate the safety, tolerability, and pharmacokinetics (PK) of BIIB033 (anti-LINGO-1 monoclonal antibody) in healthy volunteers and participants with multiple sclerosis (MS). METHODS: In 2 separate randomized, placebo-controlled studies, single ascending doses (SAD; 0.1-100 mg/kg) of BIIB033 or placebo were administered via IV infusion or subcutaneous injection to 72 healthy volunteers, and multiple ascending doses (MAD; 0.3-100 mg/kg; 2 doses separated by 14 days) of BIIB033 or placebo were administered via IV infusion to 47 participants with relapsing-remitting or secondary progressive MS. Safety assessments included adverse event (AE) monitoring, neurologic examinations, conventional and nonconventional MRI, EEG, optical coherence tomography, retinal examinations, and evoked potentials. Serum and CSF PK as well as the immunogenicity of BIIB033 were also evaluated. RESULTS: All 72 healthy volunteers and 47 participants with MS were included in the safety analyses. BIIB033 infusions were well tolerated. The frequency of AEs was similar between BIIB033 and placebo. There were no serious AEs or deaths. No clinically significant changes in any of the safety measures were observed. BIIB033 PK was similar between healthy volunteers and participants with MS. Doses of ≥10 mg/kg resulted in BIIB033 concentrations similar to or higher than the concentration associated with 90% of the maximum remyelination effect in rat remyelination studies. The incidence of anti-drug antibody production was low. CONCLUSIONS: The emerging safety, tolerability, and PK of BIIB033 support advancing BIIB033 into phase II clinical development as a potential treatment for CNS demyelination disorders. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that BIIB033 is well tolerated and safe (serious adverse event rate 0%, 95% confidence interval 0-7.6%).