This is the first time an antibody fragment has been successfully used for PET imaging of a target in the brain. The big advantage with antibodies as PET-ligands as compared to ordinary small molecular ligands is the very high specificity of antibodies. A novel method for PET imaging of the brain has been developed in Uppsala. Using BioArtic´s monoclonal antibody, mAb158, the researchers have been able to image large soluble aggregates, i.e. protofibrils, of Aβ. A large phase 2 clinical trial of Alzheimer’s disease treatment is ongoing with the humanized version of the antibody, BAN2401. The study is conducted in collaboration between Eisai and BioArctic Neuroscience.
Monoclonal antibodies are sometimes used as PET ligands to image various cancers in peripheral organs, but in the brain antibody uptake is limited by the blood-brain barrier. To increase mAb158 brain uptake, necessary for PET, a fragment of the antibody was chemically conjugated to a transferrin receptor antibody. The fusion protein displayed a 15-fold higher brain uptake and enabled visualization of the amount and the localization of protofibrils in the brain of living Alzheimer mice. The brain retention of the fusion protein and the PET signal increased with age in two different Alzheimer mouse models and correlated closely with brain levels of soluble Aβ protofibrils.
Dag Sehlin1, Xiaotian T. Fang 1, Linda Cato 1, Gunnar Antoni 2, 3, Lars Lannfelt 1, Stina Syvänen 1. Nature Communications, 2016
1 Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden.
2 Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala University, Uppsala, Sweden.
3 PET Centre, Uppsala University Hospital, Uppsala, Sweden.