Drug Development

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.