Gai Ayalon Ph.D. Neuroscientist Genentech Research and Early Development

Interception of Extracellular Tau by Antibodies May Be Sufficient to Stop the Spread of Tau in AD

Alzheimer’s disease (AD) is associated with two key pathological hallmarks: plaques and neurofibrillary tangles (NFTs). Plaques occur when a protein called amyloid-beta (Aβ) aggregates into large clumps in the extracellular space between neurons in the brain. NFTs form when a protein known as tau aggregates inside neurons.

Although both plaques and NFTs result from protein aggregation, there are some important differences between them. NFTs tend to form later in the progression of AD, closer to the onset of symptoms. Research also suggests that in AD, the anatomical distribution of tau pathology in the brain is closely related with the impairments in cognitive ability that are associated with the affected brain regions, such as planning, attention, memory, language and spatial orientation. This is different from amyloid plaques, which generally build up sporadically in the brain and years prior to the detection of any AD symptoms.

Most of the efforts to-date to develop disease-modifying therapies for AD have focused on targeting the formation of amyloid plaques and/or attempting to clear them. And although we’ve made great progress in this area, we’ve learned that to effectively treat AD we will likely need to target the spread of tau pathology, in addition to targeting Aβ.

The Effector Effect

In the past we’ve learned that therapeutic antibodies against amyloid plaques could be essential tools in the fight against AD. Now our labs and clinical development programs have extended this same strategy to potentially stop the spread of pathological tau in the brain.

Although NFTs accumulate inside neurons, research suggests that soluble species of tau can spread from cell to cell via the extracellular space. This provides an opportunity for antibodies to bind free-floating tau before it has a chance to enter a nearby neuron.

In AD, in addition to the accumulation of NFTs and plaques the brain is in a state of chronic inflammation, possibly in part due to the presence of plaques in the extracellular space. This state of inflammation is driven by the immune cells of the brain, called microglia, which release small proteins called cytokines that mediate the inflammatory response.

This state of brain inflammation in people with AD has important implications for the use of anti-tau antibodies. Once antibodies bind their target, they then bind to and get internalized by microglia, which degrade the target. But this process also elicits an inflammatory response from the microglia. The property of antibodies that mediates the binding to immune cells to promote internalization, degradation, and induction of inflammatory signals is called “effector function.” Antibody therapies for cancer, such as checkpoint inhibitors, are designed to engage precisely this aspect of the immune system. In such cases, effector function in a therapeutic antibody is highly desirable.

For AD however, there is a concern that due to existing inflammation, the activation of microglia with therapeutic antibodies could potentially be deleterious. Therefore, a key question we wanted to address was whether or not antibody effector function would be required for targeting tau effectively. We wanted to understand whether the ability to simply bind extracellular tau, without engaging the immune system, would be sufficient.

To test the importance of effector function, we engineered specific mutations in the Fc region of an anti-tau antibody that eliminated its ability to engage microglial cells. In preclinical mouse models, this “effector-less” version of the anti-tau antibody was just as effective at stopping the spread of tau as an antibody with full effector function.

These results suggest that the anti-tau antibodies from our lab can stop the spread of pathological tau simply by binding to extracellular tau, and that the additional immune stimulation of microglial cells isn’t necessary for tau clearance. Cell-based experiments further suggested that the additional inflammation induced by effector function might cause collateral damage to neurons. Given that we now know effector function is not required for targeting tau in preclinical models, our results suggest that it could be advantageous to reduce the level of antibody effector function to avoid the potential risk of aggravating brain inflammation in AD patients. This has important implications as anti-tau antibodies enter clinical experiments and may provide a safer way to target tau in a number of tauopathies, including Alzheimer’s disease. 

Gai Ayalon, Ph.D. ([email protected]), is a neuroscientist at Genentech Research and Early Development.

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