A subcutaneous cellular implant for passive immunization against amyloid-beta reduces brain amyloid and tau pathologies

Passive immunization against toxic misfolded proteins could offer protection against neurodegenerative disease. LathuiliSre et al. report the development of a retrievable device to encapsulate cells secreting recombinant anti-amyloid-beta antibodies. When implanted in mouse models of Alzheimer's disease, the system delivers antibodies to the brain and reduces amyloid and tau pathologies.Passive immunization against toxic misfolded proteins could offer protection against neurodegenerative disease. LathuiliSre et al. report the development of a retrievable device to encapsulate cells secreting recombinant anti-amyloid-beta antibodies. When implanted in mouse models of Alzheimer's disease, the system delivers antibodies to the brain and reduces amyloid and tau pathologies.Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer's disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-beta peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive cellular implant to deliver recombinant anti-amyloid-beta antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic cells over more than 10 months in immunocompetent allogeneic recipients. The encapsulated cells are genetically engineered to secrete high levels of anti-amyloid-beta antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 A mu g/ml. In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of the Alzheimer's pathology. When encapsulated cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid-beta antibodies dramatically reduces amyloid-beta(40) and amyloid-beta(42) levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho-tau pathology in the hippocampus. These results support the use of encapsulated cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer's disease and other neurodegenerative disorders.