TTP4000, a soluble fusion protein inhibitor of Receptor for Advanced Glycation End Products (RAGE) is an effective therapy in animal models of Alzheimer's disease

Abstract

RAGE is a member of the Ig supergene family that binds with nanomolar affinity to amyloid beta (Aβ) peptides which are implicated in the pathology of neurodegenerative Alzheimer's disease. RAGE expression is upregulated in Alzheimer's brains and involved in the retention of Aβ in the brain and inflammation in the neurovascular unit. Double transgenic mice that over‐express human RAGE and human amyloid precursor protein (APP) with the Swedish and London mutations in neurons develop learning defects and neuropathological abnormalities earlier than their mutant hAPP transgenic counterparts. Double transgenic mice expressing a dominant negative form of RAGE on the same mutant hAPP background, show a delayed onset of neuropathological and learning abnormalities compared to the APP transgenic background counterpart. This data suggests that interfering with RAGE signaling may have benefit in Alzheimer's disease.To test the therapeutic benefits of inhibition RAGE signaling. We have developed a novel fusion protein, TTP4000, using the binding domains of sRAGE linked to a human Ig Fc domain. TTP4000 has similar binding characteristics to ligand as sRAGE but a superior pharmacokinetic profile. We have tested TTP4000 in a mouse model of Alzheimer's disease and show that the protein is well tolerated and efficacious. TTP4000 was shown to significantly reduce soluble Aβ levels in brains of mice. The reduction of soluble brain Aβ levels correlated with a decrease in plaque load, a reduction in inflammatory cytokine levels and improved measures of behavior in the Morris Water Maze test. These data confirm and extend previous reports implicating RAGE in the pathogenesis of Alzheimer's disease and indicate that TTP4000, an injectable RAGE antagonist, is a viable treatment for Alzheimer's disease.