Gantenerumab

Alzheimer's disease (AD) is the most common cause of dementia in elderly patients, characterized by behavioural, psychological, and cognitive alterations underpinned by neurodegeneration. The classical histopathological hallmarks of AD include extracellular amyloid-beta (Aβ) plaques derived from amyloid precursor protein (APP), and intraneuronal neurofibrillary tangles (NFTs), containing aggregated hyperphosphorylated tau protein. APP is an ~120 kDa protein that can be cleaved through either a non-amyloidogenic (physiological) or amyloidogenic (pathological) pathway, the latter producing Aβ peptides of varying length (Aβ40, Aβ42, and Aβ43) that self-assemble into oligomers and subsequently into insoluble fibrillar aggregates of unique structure.

The classical view of AD progression, the amyloid cascade hypothesis, posits that Aβ accumulation triggers tau hyperphosphorylation and aggregation, which causes much of the pathology, potentially through mechanisms involving mitochondrial homeostasis. However, various observations are difficult to reconcile with this hypothesis fully. Aβ plaques are frequently observed in individuals without apparent cognitive impairment, and the most cytotoxic species appear to be small (2-10mer) Aβ oligomers rather than fibrillar plaques. While in vitro studies have confirmed the ability of Aβ oligomers to induce tau aggregation, the reverse also appears to hold. Interestingly, consistent with the differential localization of Aβ and tau aggregates, there is a low (0.02%) synaptic overlap between the two markers. Finally, despite the development of numerous agents targeting the synthesis and aggregation of Aβ or directly clearing Aβ plaques, the majority of clinical studies to date have shown little to no clinical benefit in AD patients.

Gantenerumab is a fully human IgG1κ monoclonal antibody recognizing a unique conformational Aβ epitope including N-terminal and central amino acids that are spatially juxtaposed in Aβ oligomers and fibrils. As such, gantenerumab displays kinetically stable binding to Aβ40 oligomers (KD 1.2 nM, kd 4.9 x 10-4 s-1) and fibrils (KD 0.6 nM, kd 2.8 x 10-4 s-1) with less stable binding to monomers (KD 17 nM, kd 1.2 x 10-2 s-1). In vitro experiments involving co-incubation of gantenerumab with microglial cells and macrophages revealed a minimum effective concentration of 0.07 nM and an EC50 of 0.7 nM for Aβ plaque removal; a combination of in vitro and in vivo studies have revealed the requirement for effector cells, suggesting Aβ plaque removal by gantenerumab is primarily mediated by phagocytosis and intracellular degradation.