Affinity of Tau antibodies for solubilized pathological Tau species but not their immunogen or insoluble Tau aggregates predicts in vivo and ex vivo efficacy

Abstract

BackgroundA few tau immunotherapies are now in clinical trials with several more likely to be initiated in the near future. A priori, it can be anticipated that an antibody which broadly recognizes various pathological tau aggregates with high affinity would have the ideal therapeutic properties. Tau antibodies 4E6 and 6B2, raised against the same epitope region but of varying specificity and affinity, were tested for acutely improving cognition and reducing tau pathology in transgenic tauopathy mice and neuronal cultures.ResultsSurprisingly, we here show that one antibody, 4E6, which has low affinity for most forms of tau acutely improved cognition and reduced soluble phospho-tau, whereas another antibody, 6B2, which has high affinity for various tau species was ineffective. Concurrently, we confirmed and clarified these efficacy differences in an ex vivo model of tauopathy. Alzheimer’s paired helical filaments (PHF) were toxic to the neurons and increased tau levels in remaining neurons. Both toxicity and tau seeding were prevented by 4E6 but not by 6B2. Furthermore, 4E6 reduced PHF spreading between neurons. Interestingly, 4E6’s efficacy relates to its high affinity binding to solubilized PHF, whereas the ineffective 6B2 binds mainly to aggregated PHF. Blocking 4E6's uptake into neurons prevented its protective effects if the antibody was administered after PHF had been internalized. When 4E6 and PHF were administered at the same time, the antibody was protective extracellularly.ConclusionsOverall, these findings indicate that high antibody affinity for solubilized PHF predicts efficacy, and that acute antibody-mediated improvement in cognition relates to clearance of soluble phospho-tau. Importantly, both intra- and extracellular clearance pathways are in play. Together, these results have major implications for understanding the pathogenesis of tauopathies and for development of immunotherapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0126-z) contains supplementary material, which is available to authorized users.

Tau Immunotherapies for Alzheimer’s Disease and Related Tauopathies: Progress and Potential Pitfalls1

“…In later studies, we showed that tau antibodies could have the same effect [5,6], and provided various insights into the possible mechanisms of clearance [7–19]. These studies have been confirmed and extended by various groups showing benefits of immune-targeting the pS396/404 tau epitope [2,4,6–9,12,20–27], and other tau epitopes [20,23–25,27–49], which as mentioned above has resulted in eight clinical trials (for a recent review of these trials see [50]), with several more likely to be initiated in the near future. We have highlighted many of these studies in some details in various reviews over the years as they have been reported so it is not necessary to elaborate further on those particular aspects (see for example [51–53]).…”

“…However, other features have been less studied and have sometimes led to surprising results. For example, we have shown that a low affinity antibody is more effective than a high affinity antibody against the same region [12]. However, this is a complex issue as these antibodies are likely conformational to some extent and recognize different tau species [12], which may have different degree of importance for tau pathogenesis.…”

“…For example, we have shown that a low affinity antibody is more effective than a high affinity antibody against the same region [12]. However, this is a complex issue as these antibodies are likely conformational to some extent and recognize different tau species [12], which may have different degree of importance for tau pathogenesis. The potential influence of antibody size has not been well studied but we have shown that it greatly affects antibody uptake into neurons and not necessarily as you would expect [9,11].…”

“…Finally, the importance of antibody charge for intracellular access has been well studied for potential cancer antibody therapies but not for tau antibodies or similar approaches targeting other amyloids. We have recently shown that antibody charge can robustly affect antibody uptake into neurons [19,64], which may explain why some labs detect tau antibodies inside neurons [2,7–9,11,12,14,39,40,65], whereas others do not for different antibodies [34,41,43]. This issue has particular importance for clinical trials because the humanized antibodies are likely to have a different charge than the mouse antibodies that they are based on.…”

“…The epitope that was a part of the immunogen in our original report has been most studied and repeatedly shown to be a good target [2,4,6–9,12,15,20–27]. …”