Alzheimer's disease is characterized by the aggregation of first amyloid-β and then tau protein in later stages. It took many years and many attempts to produce immunotherapies capable of clearing amyloid-β from the brain, only to find that this doesn't in fact help patients to any great degree. Amyloid-β may be a side-effect of the causative mechanisms - such as infection, or chronic inflammation - or only important in the earliest stages of the development of Alzheimer's. By the time tau aggregation happens, a different disease process has become dominant. One of the next options is to target tau protein with the same sorts of immunotherapy technologies. So far this is proceeding in much the same way, with the first attempts failing to achieve meaningful levels of clearance.
With anti-amyloid antibodies now consistently hitting their target, tau immunotherapy represents the next frontier. In Alzheimer's disease, tau tangles correlate far more closely with cognitive decline than plaques do, and tau aggregates are the main pathology in many related disorders. As with amyloid, however, initial trials of anti-tau antibodies have been beset by failures. Already, several antibodies that bind the N-terminus or C-terminus of tau have been scuttled after not doing recipients any good. Meanwhile, preclinical evidence suggests that antibodies that go after the protein's mid-section, particularly its microtubule-binding region (MTBR), may be better at preventing aggregates from spreading. Several such antibodies have now entered Phase 1 or 2.
At the 15th International Conference on Alzheimer's and Parkinson's Diseases, researchers discussed a number of these programs. Roche offered a first look at biomarker data from the negative Phase 2 trial of the N-terminal-targeting antibody semorinemab. Other speakers touted MTBR-binding antibodies. Pinteon Therapeutics showed preliminary Phase 1 findings for PNT001, while the Technical University of Munich presented on UCB's beprenemab, also in Phase 1. Prothena's MTBR-binder PRX005 is still preclinical, but the company offered mechanistic data on how it might inhibit the transfer of pathological tau.
Time will tell if this newest crop can perform in the clinic. Researchers believe the field is making progress in figuring out how to target the protein, and are encouraged by cerebrospinal fluid data that link cerebrospinal fluid MTBR tau with tangles, and specific tau phospho-species with plaques. "That's really exciting for us as a field. We're learning so much more about this target."