AL001 Blocks the Sortilin/PGRN Interaction and is a Potential Therapy for FTD-GRN (4422)

Objective: AL001 blocks the Sortilin/PGRN interaction and is a potential therapy for FTD-GRN Background: Frontotemporal dementia (FTD) is a rare, early-onset form of dementia that presents with marked changes in personality, speech, executive function, and movement. Heterozygous loss-of-function GRN mutations in the progranulin gene (GRN) causes a more than 50% reduction in secreted functional progranulin protein (PGRN) and almost invariably lead to development of FTD, making GRN a causal gene for the disease. Therefore, elevating functional PGRN levels in individuals carrying GRN mutations causative of FTD (FTD-GRN individuals) may be a viable therapeutic strategy. In the brain, PGRN is expressed primarily by neurons and microglia and is involved in neuronal survival, neurite outgrowth, and synaptogenesis and is a key regulator of neuroinflammation and lysosomal function. The Sortilin receptor has been identified as the major regulator of PGRN levels. Sortilin binds extracellular PGRN and mediates its endocytosis and metabolism via lysosomes. Therefore, blocking Sortilin/PGRN interactions provides a therapeutic strategy for sustaining levels of functional secreted PGRN in the central nervous system (CNS) with the potential to minimize progression of FTD-associated dementias. Design/Methods: Alector has generated a therapeutic candidate human recombinant monoclonal antibody, AL001, that binds specifically to human Sortilin. Results: AL001 effectively binds Sortilin with a high affinity and blocks the interaction between PGRN and Sortilin receptor. Blocking Sortilin with the AL001 antibody increases PGRN levels in plasma and cerebrospinal fluid (CSF) in non-human primate models, healthy volunteers, and heterozygous carriers of GRN mutations. Conclusions: AL001 is being developed for the treatment of carriers of GRN mutations causative of FTD to reduce the rate of neurodegeneration by increasing levels of PGRN in the periphery and the brain. Disclosure: Dr. Paul has received personal compensation for serving as an employee of Alector. Dr. Paul has received stock or an ownership interest from Alector. Hua Long has received personal compensation for serving as an employee of Alector. Hua Long has received stock or an ownership interest from Alector. Hua Long has received intellectual property interests from a discovery or technology relating to health care. Guang Tu has received personal compensation for serving as an employee of Alector. Guang Tu has received stock or an ownership interest from Alector. Dr. Haynes has received personal compensation for serving as an employee of Alector, Inc.. Michael WARD has received personal compensation for serving as an employee of Alector. Michael WARD has received stock or an ownership interest from Alector. Michael WARD has received intellectual property interests from a discovery or technology relating to health care. Michael WARD has a non-compensated relationship as a Reviewer with ADDF that is relevant to AAN interests or activities. Dr. McCaughey has received personal compensation for serving as an employee of Alector, Inc. Dr. McCaughey has received stock or an ownership interest from Alector, Inc. Mackenzie Hagey has received personal compensation for serving as an employee of Alector. Michael Kurnellas has received personal compensation for serving as an employee of Alector. Michael Kurnellas has received stock or an ownership interest from Alector. Michael Kurnellas has received intellectual property interests from a discovery or technology relating to health care. Tina Schwabe has received personal compensation for serving as an employee of Alector. An immediate family member of Tina Schwabe has received personal compensation for serving as an employee of Coda Biotherapeutics. Tina Schwabe has received stock or an ownership interest from Alector. An immediate family member of Tina Schwabe has received stock or an ownership interest from Coda Biotherapeutics. Tina Schwabe has received intellectual property interests from a discovery or technology relating to health care.