P3‐283: Selection of an anti‐Abeta antibody that binds various forms of Abeta and blocks toxicity both in vitro and in vivo

• DOI: 10.1016/j.jalz.2009.04.954
• Publication Date: 2009-06-25T11:25:15Z
• Authors: Ryan J. Watts; Mark Chen; Jasvinder Atwal; Joan M. Greve; Yongjian Wu; Deborah L. Mortensen; Yvan Varisco; Oskar Aldolfsson; Maria Pihlgren; Andrea Pfeifer; Andreas Muhs
• Keywords: Humanized antibody

After a decade of research on immunological approaches to treating Alzheimer's disease (AD), much has been learned about selection criteria for antibodies targeting β-amyloid (Abeta). Here we describe the preclinical properties an anti-Abeta MAb, MABT5102A, which selected testing as modifying therapeutic in patients with AD. Monoclonal (MAbs) were generated by immunization mice pegylated Abeta peptide integrated into liposomes. Murine MAbs further characterized using both vitro and vivo methods evaluate binding toxicity. An MAb was then humanization affinity maturation evaluated PKPD models. A parental murine that bound multiple forms Abeta. Treatment this showed increase cognitive memory capacity animal model AD (hAPP-Tg). Long-term dosing studies aged mouse resulted reduction plaque load number. This matured humanized give rise MABT5102A. In vitro, MABT5102A equally well high monomer-, oligomer- fiber-enriched preparations Abeta1-42 peptide. Furthermore, inhibited self-association aggregation peptides protofibrillar conformations, it disaggregated pre-formed protofibrils. also blocked oligomer-induced toxicity primary neurons. safety supported initiation phase I clinical trials. monoclonal antibody, based various desirable is currently study enrolling mild moderate patients.