Epitope-Specific Targeting of Tau Aggregates

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Ten tau immunotherapies are currently in clinical trials. One of the most studied tau epitopes preclinically, including in our original reports, phospho-serine 396,404, is being targeted in two of these trials. We have generated several antibodies against it, which have unique binding profiles to these two phospho- sites and varying efficacy in preventing tau toxicity and promoting tau clearance. It is not clear why the subtle epitope differences within this region can greatly influence antibody efficacy. Another important issue to explore is which antibody isotype to choose for clinical trials. To date, these have either strong or limited effector function with regard to promoting microglial phagocytosis of the tau-antibody complex, but this key isotype efficacy/safety issue has not been well examined in tauopathy models. The few reports on it differ in their conclusion. A third matter that needs to be studied further has to do with where to target pathological tau, intra- and/or extracellularly. Most companies have focused on extracellular clearance but since almost all of pathological tau resides intracellularly (>99%), targeting it there in addition to extracellularly should be more efficacious, as we have advocated over the years. Specifically, we have shown that neuronal uptake of tau antibodies and thereby their efficacy in clearing tau and preventing its toxicity is influenced by their electrical charge. The relationship between antibody charge and efficacy has been well studied in the cancer field but has received little attention in the tau field. Finally, it is not clear which forms of tau are most toxic and should ideally be targeted with therapies. Our recent preliminary data indicates that we have been able to stabilize a toxic conformation of tau. We would like to clarify this phenomenon, which may have major implications for understanding tau pathogenesis and for development of therapies. To address these related very important issues we propose to clarify: 1) the pronounced influence of subtle epitope differences and antibody isotype on the efficacy of tau antibodies; 2) the robust influence of affinity and electrical charge on antibody efficacy, and; 3) why engineering an effective single domain tau antibody (sdAb) to a full size antibody (Fc-(sdAb)2 renders it toxic, whereas the same modification for a different effective tau sdAb does not. The scientific premise of these aims is highly supported by our publications and preliminary data, and the approach is very feasible based on this foundation and the use of technologies that are well established in our laboratories, reflecting strong rigor and reproducibility. Together, the outcome of these studies is likely to guide further development of tau immunotherapies and provide valuable insight into tau pathogenesis in Alzheimer's disease and related tauopathies that may be applicable to other targets in various protein aggregation diseases.