PROJECT SUMMARY For 22 years, the Nonhuman Reagent Resource (NHPRR) has produced and distributed high quality NHP antibodies to NIH investigators where there are no commercial alternatives. Although most program reagents were validated and engineered for use in Old World species that are commonly used in preclinical biomedical research, a new targeted effort, funded through the R24 mechanism, was launched in 2020 to create and characterize antibodies for New World primate studies. This grant covers the development and production of squirrel monkey and marmoset monospecific immunoglobulins that are suitable for in vivo administration and carefully monitored for contaminants that can compromise animal safety and experimental integrity. Squirrel monkeys are natural NHP models for Alzheimer’s disease (AD) due to an age-associated neurodegenerative decline that pathologically resembles AD with cerebral amyloid angiopathy (CAA). One formidable barrier to applying immunotherapeutics, other macromolecular drugs, or even some small molecule inhibitors to treat AD is the impenetrable nature of the blood-brain barrier (BBB) that excludes most drugs from the brain parenchyma. In this supplement application, we propose to develop a bispecific antibody capable of transversing the BBB through receptor-mediated transport (RMT) and targeting AD-relevant protein beta-secretase (BACE1). This reagent will be rigorously tested in vitro and in vivo to measure any therapeutic gains through RMT and validate the technology in squirrel monkeys. The final RMT-BACE1 squirrel monkey IgG will be offered and distributed to AD investigators through the program website. Furthermore, this effort will establish methods to generate RMT bispecific antibodies for neotropical primate immunoglobulins that can be broadly applied to other AD immunotherapy candidates or imaging studies.