Journal
MOLECULAR PHARMACEUTICS
Volume 10, Issue 9, Pages 3507-3513Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp400348n
Keywords
blood-brain barrier; Alzheimer's disease; amyloid; transferrin receptor; monoclonal antibody
Funding
- National Institutes of Health National Institute of Aging [R01-AG032244]
Ask authors/readers for more resources
Anti-amyloid antibodies (AAA) are under development as new therapeutics that disaggregate the amyloid plaque in brain in Alzheimer's disease (AD). However,: the AAAs: are large, :molecule drugs that do not cross the blood brain barrier (BBB), in the absence of BBB disruption. In the present study, an AAA was re engineered for receptor mediated transport across the BBB via the endogenous BBB transferrin receptor (TfR). A single chain Fv (ScFv) antibody form of. an AAA was fused to the :carboxyl terminus of each heavy chain of a chimeric monoclonal antibody (mAb) against the Mouse TfR, and this produced a tetravalent bispecific; antibody designated the cTfRMAb-ScFv fusion protein. Unlike a conventional AAA, which has a plasma half-time of weeks, the cTfRMAb-ScFv fusion protein is cleared from plasma in mice with a mean residence time of about 3 h. Therefore, a novel protocol was developed for the treatment of one year old:presenilin (PS)-1/amyloid precursor protein (APP) AD double transgenic PSAPP mice, which were administered daily subcutaneaus (sc) injections of 5 mg/kg of the cTfRMAb-ScFv fusion protein for 12 consecutive weeks: At the end Of the treatment, brain amyloid plaques were quantified with confocal microscopy using both Thioflavin-S staining and immunostaining with, the 6E10 antibody against Abeta amyloid fibrils. Fusion protein treatment caused a 5746 and 0146 reduction in amyloid plaque in the cortex and hippocampus, respectively. No increase in plasma immunoreactive Abeta amyloid peptide, and no cerebral microhemorrhage, was observed Chronic daily sc treatment of the mice with the fusion protein Caused: no immune reactions and Only a low titer antidrug antibody response. In conclusion, re-engineering AAAs for receptor-mediated BBB transport allows for reduction in brain amyloid plaque Without cerebral. microhemorrhage following daily sc treatment for 12 weeks
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available