TTP4000 and related biologics were created in order to combine the therapeutic potential of sRAGE with the desirable pharmacokinetic profile of immunoglobulin fusion proteins.The receptor for advanced glycation endproducts (RAGE) is an immunoglobulin supergene family member. RAGE is expressed on multiple cell types including vascular endothelium, macrophages, podocytes, neurons, and microglial cells and is promiscuous in that it binds multiple functionally and structurally diverse ligands including amyloid beta (Aβ), advanced glycation endproducts (AGEs), S100 (proinflammatory member of the calgranulin family), serum amyloid A (SAA), and amphoterin. These interactions initiate signal transduction pathways including the activation of the transcriptional mediator of inflammatory signaling, NF-kB.  Furthermore, RAGE expression is upregulated at sites of inflammation or oxidative stress.

RAGE was initially identified as a receptor for AGEs, molecules whose expression are upregulated in diabetes and associated with the pathology of diabetic complications.  Subsequent studies have demonstrated that RAGE itself is essential to the pathophysiology of diabetic complications and multiple other diseases characterized by inflammation or oxidant stress.  RAGE activation has been linked to ischemia/reperfusion injury and to the pathogenesis of autoimmune disease and chronic inflammation. Subsequent research demonstrated a critical role for RAGE in the pathophysiology of Alzheimer’s disease.  RAGE is a receptor for Aβ as well as other amyloidogenic proteins including SAA and amylin. 

Since TTP4000 has a similar profile as sRAGE in terms of binding to RAGE ligands and inhibiting RAGE/ligand signaling, and since TTP4000 proved efficacious in a mouse model of AD, there is a clear rationale to evaluate TTP4000 in the clinic for the treatment of AD.
 
Furthermore, since TTP4000 is expected to behave like sRAGE in terms of efficacy and have a pharmacokinetic profile similar to that of other IgG1 fusion proteins in man, including a half-life of greater than one week, it is anticipated that TTP4000 may prove efficacious in other pathologies where sRAGE has been shown to attenuate the pathology, including diabetic complications or RAGE-mediated vascular disease. 

TTP4000 administered in animal models of AD have reduced both amyloid burden and Aβ phenotypes in the brains of treated animals. In addition, TTP4000 was associated with a marked improvement in cognitive function with the animals evaluated.