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1.
Acta Neuropathol Commun ; 6(1): 59, 2018 07 12.
Article in English | MEDLINE | ID: mdl-30001207

ABSTRACT

Aggregation of tau protein and spreading of tau aggregates are pivotal pathological processes in a range of neurological disorders. Accumulating evidence suggests that immunotherapy targeting tau may be a viable therapeutic strategy. We have previously described the isolation of antibody CBTAU-22.1 from the memory B-cell repertoire of healthy human donors. CBTAU-22.1 was shown to specifically bind a disease-associated phosphorylated epitope in the C-terminus of tau (Ser422) and to be able to inhibit the spreading of pathological tau aggregates from P301S spinal cord lysates in vitro, albeit with limited potency. Using a combination of rational design and random mutagenesis we have derived a variant antibody with improved affinity while maintaining the specificity of the parental antibody. This affinity improved antibody showed greatly enhanced potency in a cell-based immunodepletion assay using paired helical filaments (PHFs) derived from human Alzheimer's disease (AD) brain tissue. Moreover, the affinity improved antibody limits the in vitro aggregation propensity of full length tau species specifically phosphorylated at position 422 produced by employing a native chemical ligation approach. Together, these results indicate that in addition to being able to inhibit the spreading of pathological tau aggregates, the matured antibody can potentially also interfere with the nucleation of tau which is believed to be the first step of the pathogenic process. Finally, the functionality in a P301L transgenic mice co-injection model highlights the therapeutic potential of human antibody dmCBTAU-22.1.


Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Antibodies/pharmacology , Brain/metabolism , Serine/metabolism , tau Proteins/immunology , tau Proteins/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/metabolism , Animals , Antibody Affinity/drug effects , Autopsy , Brain/pathology , Dose-Response Relationship, Drug , Epitopes/metabolism , Female , Humans , Male , Mice , Mice, Transgenic , Microscopy, Atomic Force , Middle Aged , Models, Molecular , Mutagenesis , Mutation/genetics , Phosphorylation/physiology , Protein Aggregation, Pathological/metabolism , Protein Aggregation, Pathological/pathology , Protein Aggregation, Pathological/therapy
2.
Acta Neuropathol ; 133(5): 767-783, 2017 05.
Article in English | MEDLINE | ID: mdl-28341999

ABSTRACT

Several reports have described the presence of antibodies against Alzheimer's disease-associated hyperphosphorylated forms of tau in serum of healthy individuals. To characterize the specificities that can be found, we interrogated peripheral IgG+ memory B cells from asymptomatic blood donors for reactivity to a panel of phosphorylated tau peptides using a single-cell screening assay. Antibody sequences were recovered, cloned, and expressed as full-length IgGs. In total, 52 somatically mutated tau-binding antibodies were identified, corresponding to 35 unique clonal families. Forty-one of these antibodies recognize epitopes in the proline-rich and C-terminal domains, and binding of 26 of these antibodies is strictly phosphorylation dependent. Thirteen antibodies showed inhibitory activity in a P301S lysate seeded in vitro tau aggregation assay. Two such antibodies, CBTAU-7.1 and CBTAU-22.1, which bind to the proline-rich and C-terminal regions of tau, respectively, were characterized in more detail. CBTAU-7.1 recognizes an epitope that is similar to that of murine anti-PHF antibody AT8, but has different phospho requirements. Both CBTAU-7.1 and CBTAU-22.1 detect pathological tau deposits in post-mortem brain tissue. CBTAU-7.1 reveals a similar IHC distribution pattern as AT8, immunostaining (pre)tangles, threads, and neuritic plaques. CBTAU-22.1 shows selective detection of neurofibrillary changes by IHC. Taken together, these results suggest the presence of an ongoing antigen-driven immune response against tau in healthy individuals. The wide range of specificities to tau suggests that the human immune repertoire may contain antibodies that can serve as biomarkers or be exploited for therapy.


Subject(s)
Alzheimer Disease/immunology , Epitopes/immunology , Immunologic Memory/immunology , Neurofibrillary Tangles/immunology , tau Proteins/metabolism , Adolescent , Adult , Aged , Amino Acid Sequence/physiology , Antibodies, Monoclonal/immunology , Binding Sites , Epitopes/metabolism , Female , Humans , Male , Middle Aged , Neurofibrillary Tangles/pathology , Phosphorylation , Young Adult
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