Passive immunotherapies targeting Aβ and tau in Alzheimer's disease

Abstract

Amyloid- β (A β ) and tau proteins currently represent the two most promising targets to treat Alzheimer's disease. The most extensively developed method to treat the pathologic forms of these proteins is through the administration of exogenous antibodies, or passive immunotherapy. In this review, we discuss the molecular-level strategies that researchers are using to design an effective therapeutic antibody, given the challenges in treating this disease. These challenges include selectively targeting a protein that has misfolded or is pathological rather than the more abundant, healthy protein, designing strategic constructs for immunizing an animal to raise an antibody that has the appropriate conformational selectivity to achieve this end, and clearing the pathological protein species before prion-like cell-to-cell spread of misfolded protein has irreparably damaged neurons, without invoking damaging inflammatory responses in the brain that naturally arise when the innate immune system is clearing foreign agents. The various solutions to these problems in current clinical trials will be discussed.

Targeting Tau to Treat Clinical Features of Huntington's Disease

“…Antibodies are now available to recognize a diversity of extracellular tau isoforms and fragments. The antibody C2N-8E12 (also referred to as ABBV-8E12) recognizes the isoform tau-F (441 aa) (200), while the antibody RO7105705 (also referred to as Semorinemab) binds the N-terminus of all six tau isoforms (201). Gosuranemab (also referred to as BMS-986168) was engineered using a tau fragment released into the conditioned media prepared from AD patient-derived cortical neurons (202,203).…”

Passive Immunization With a Novel Monoclonal Anti-PrP Antibody TW1 in an Alzheimer’s Mouse Model With Tau Pathology

“…Despite showing success in many AD models immunotherapy targeting Aβ has failed in clinical trials thus far (Reiss et al, 2020;Vaz and Silvestre, 2020). Immunotherapy addressing tau pathology has been less extensively investigated, but may represent a better target, since this pathology correlates better with AD cognitive symptoms (Nelson et al, 2012;Götz and Götz, 2019;Plotkin and Cashman, 2020;Soeda and Takashima, 2020).…”

“…Tau pathology targeted immunotherapy is a less explored area of investigation compared to Aβ targeted approaches; however, it is a very active area of study with two trials of active immunization and ten on-going passive immunization trials (Götz and Götz, 2019;Plotkin and Cashman, 2020;Soeda and Takashima, 2020;Vander Zanden and Chi, 2020). An important criterion for this approach is that the immune response generated must avoid interacting with native, monomeric tau in neurons; hence, the majority of the anti-tau antibodies being tested are more specific to aggregated, oligomeric tau species (Plotkin and Cashman, 2020;Soeda and Takashima, 2020;Vander Zanden and Chi, 2020). These anti-tau antibodies aim to mainly act in the extracellular space, to stop the prion-like spread of tau oligomer pathology.…”

“…Numerous studies of passive immunization with anti-amyloid (Aβ) antibodies have demonstrated effective clearance of amyloid Aβ together with cognitive improvements in transgenic animal models (Herline et al, 2018a;Kwon et al, 2020). However, active and passive immunization targeting Aβ has failed in all clinical trials thus far, with the possible recent exception of aducanumab (Loureiro et al, 2020;Plotkin and Cashman, 2020), an antibody that is more specific to insoluble fibrillary and oligomeric forms of Aβ (Arndt et al, 2018;Tolar et al, 2020). There is a growing realization that the most toxic species of Aβ are oligomeric (Viola and Klein, 2015); similarly, it is also thought that oligomeric species of other proteins (i.e., tau, α-synuclein, TDP-43, etc.)…”

Antibody Fragments as Tools for Elucidating Structure-Toxicity Relationships and for Diagnostic/Therapeutic Targeting of Neurotoxic Amyloid Oligomers

“…Methodologies for rational Aβ-targeting antibody design have been reviewed (e.g., Plotkin and Cashman, 2020 [ 131 ]). For example, just as our group has successfully generated full-length IgGs with selectivity for AβOs over monomers and fibrils [ 132 ], rational immunization with specific toxic AβO species can be employed, followed by conversion of the resulting anti-AβO IgG to an antibody fragment.…”