Professor University of Michigan Ann Arbor, Michigan, United States
Introduction: : Neuroinflammation contributes significantly to the progression of CNS disorders such as multiple sclerosis, Alzheimer’s disease, and traumatic brain injury, yet current therapies and imaging techniques are limited by their inability to target pathogenic immune cells within the CNS due to the restrictive blood-brain barrier (BBB). Current imaging strategies often lack specificity for microglial activation and fail to detect peripheral immune cell infiltration. CD11b, a surface integrin expressed on microglia and infiltrating leukocytes, represents a compelling molecular target for neuroinflammatory imaging. In this work, we developed a bispecific antibody (BsAb) that targets CD11b and transferrin receptor 1 (TfR-1), enabling transport across the BBB and localization to neuroinflammatory sites.
Materials and
Methods: : A bispecific antibody was engineered to simultaneously bind CD11b and TfR-1. Acute neuroinflammation was induced in mice via intrastriatal injection of lipopolysaccharide (LPS, 5 µg). Antibody distribution was assessed using immunohistochemistry, flow cytometry, and PET/CT imaging following administration of ⁸⁹Zr-labeled proteins. We compared CD11b/TfR-1 BsAbs to control antibodies including IgG/TfR-1 and CD11b/IgG. Fluorescence intensity, cellular localization, and brain uptake were analyzed at multiple timepoints post-injection.
Results, Conclusions, and Discussions:: CD11b/TfR-1 BsAbs demonstrated time-dependent redistribution from brain endothelium to microglia, as shown by immunostaining and flow cytometry. Compared to controls, BsAbs exhibited significantly greater CNS penetration and selective engagement with microglia and leukocytes. PET/CT imaging confirmed enhanced signal in the brain parenchyma, validating target engagement. These findings highlight the potential of TfR-1-mediated shuttling to overcome BBB limitations and improve the sensitivity and specificity of neuroinflammatory imaging. Future work will focus on optimizing antibody design and extending applications to chronic and disease-specific models.
