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Among the different immunotherapies currently in development against Alzheimer's disease (AD), antibodies against specific forms of Aβ peptides have gained considerable interest. For example, post-translationally modified Aβ peptides with a pyroglutamate at the N-terminus (pGlu3) are attractive targets, due to their neoepitope character and their enhanced propensity to form neurotoxic oligomeric aggregates, which are associated with cognitive decline. A novel anti-pGlu3-Aβ antibody, PBD-C06, was generated by first grafting CDR regions from a murine precursor antibody onto suitable human variable light and heavy chains. Subsequently, the humanized antibody was de-immunized by eliminating potential T cell epitopes. In addition, site-specific mutations were introduced to the framework sequence to optimize target binding, to eliminate complement activation and to improve protein stability. A target binding profile of PBD-C06 against monomeric, oligomeric and fibrillar Aß-species was determined in Biacore analyses. C1q binding was tested by ELISA and preservation of effector function (ADCC) was analyzed in Fcγ-receptor binding and phagocytosis studies. Comparability between the murine precursor and final antibody was determined in binding and IHC studies. PBD-C06 binds with high specificity to pGlu3-Aβ monomers, oligomers and fibrils, including mixed aggregates of unmodified Aβ and pGlu3-Aβ peptides. Based on epitope binding analyses a back-mutation within the VH framework sequence was introduced to restore affinity partially lost during the humanization procedure. Elimination of C1q binding within the Fc-region of PBD-C06 did not compromise Fcγ-receptor binding or in vitro phagocytosis. The final antibody, PBD-C06, binds with the same specificity as the murine precursor and displays a comparable staining profile for pGlu3-Aβ in human AD brain sections. Here, we describe a novel humanized IgG1 antibody, PBD-C06, that specifically targets neurotoxic aggregates containing pGlu3-Aβ. PBD-C06 was de-immunized and modified to avoid complement-mediated inflammatory responses, to lower the risk for ARIA-E and achieve a favorable safety profile in the clinic.