Generation and Characterization of Nanobodies Against beta-Amyloid

DESCRIPTION provided by applicant Alzheimerandapos s disease AD is the most common dementia in the elderly and imposes a tremendous burden to patientsandapos families and the society both financially and emotionally Currently there is no effective treatment available to cure the disease Pathologically AD is characterized by the presence of extracellular amyloid A plaques and intracellular tau neurofibrillary tangles in selected brain regions including cerebral cortex and hippocampus Multiple strategies targeting on A generation and clearance are being pursued vigorously in an effort to reduce A levels and A induced synaptic and neuronal toxicity However these attempts including those using anti A immunotherapies have not led to any FDA approved drugs to treat AD mainly due to toxic side effects and lack of efficacy Despite these failures anti A based immunotherapies have made progress Crenezumab a humanized monoclonal antibody targeting both monomeric and oligomeric forms of A by Genentech Roche inhibits A aggregation and promotes A disaggregation Although it missed its primary endpoints in a lately completed Phase II clinical trial crenezumab treatment in people with mild to moderate AD showed a trend toward slowing cognitive decline Most recently Biogen Idec has announced positive results from a Phase b clinical trial on its pipeline drug candidate aducanumab a human monoclonal antibody that binds aggregated forms of A with high affinity and plans to carry out a phase III study Therefore anti A immunotherapies are highly promising and improved anti A therapeutic reagents can help bring such therapies into clinic The purpose of this proposed project is to generate an advanced nano antibody for reducing amyloid A levels and preventing A plaque formation in AD Nan antibody nAb is a distinctive type of antibody fragment derived from camelid heavy chain only antibody HCAb As a therapeutic candidate nAb holds many superior properties that may enable some key improvement of current anti A reagents to help them succeed in clinical trials In this proposal we will develop engineered nano antibodies that will bind A and target it for degradation We will test the efficacy of such anti A reagents in cell and mouse models of Alzheimerandapos s disease We expect that this engineered anti A nAbs to have higher A binding affinity and greater A reduction efficiency but less toxic side effects compared to conventional antibodies PUBLIC HEALTH RELEVANCE Targeting amyloid peptide in its monomer form or aggregated form has the potential of slowing the progression of Alzheimerandapos s disease We propose to develop amyloid peptide targeting reagents by combining the specificity of novel nano antibodies or nanobodies and cellular degradation signals The work in this proposal can lay a foundation for further development of such reagents for clinical use