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Summary
This summary is machine-generated.

Tissue clearing and light sheet microscopy enable whole-brain imaging of therapeutic antibody biodistribution in preclinical models. This technology allows for precise quantification of drug delivery and target engagement in the brain, aiding CNS therapeutic development.

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Biotechnology

Background:

  • Traditional histology requires tissue slicing, limiting comprehensive analysis of intact organs.
  • Tissue clearing offers neuroscientists complete, unbiased views of brain anatomy and function.
  • Tissue clearing is valuable for CNS therapeutic development, enabling examination of drug distribution.

Purpose of the Study:

  • To develop and validate a pipeline for cellular-resolution, brain-wide measurement of therapeutic biodistribution in rodent models.
  • To assess the utility of tissue clearing for detecting antibody therapeutics crossing the blood-brain barrier (BBB) and engaging CNS targets.

Main Methods:

  • Utilized an iDISCO-based tissue clearing method combined with light sheet microscopy for imaging intact mouse brains.
  • Employed an AI-powered quantification pipeline to segment and measure antibody staining in both vasculature and brain parenchyma.
  • Investigated antibody delivery using both a bispecific antibody targeting BACE1 and TfR1, and a Donanemab biosimilar in Alzheimer's Disease models.

    • Main Results:

    • A bispecific antibody crossed the BBB and engaged BACE1 targets in the parenchyma, while a monospecific antibody did not reach the brain parenchyma.
    • Quantification pipeline successfully measured parenchymal levels of the bispecific antibody, distinguishing it from vascular signal.
    • Donanemab biosimilar accumulated in the brain of AD model mice, crossing the BBB and localizing with amyloid plaques, unlike in wild-type mice.

    Conclusions:

    • Tissue clearing methods provide a powerful tool for quantitative, whole-brain monitoring of therapeutic antibody biodistribution.
    • Demonstrated the capability to track CNS therapeutic delivery and target engagement with cellular resolution.
    • Highlights the potential of this technology for advancing Alzheimer's Disease therapeutic development and preclinical research.