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General Description:

Gantenerumab, identified by CAS number 1043556-46-2, is a notable compound with significant therapeutic applications. Alzheimer's disease (AD) is the most common cause of dementia in elderly patients, with classical histopathological hallmarks including extracellular amyloid-beta (Aβ) plaques and intraneuronal neurofibrillary tangles (NFTs). As the classical view of AD pathology posits that Aβ accumulation triggers tau hyperphosphorylation and aggregation to form NFTs and cause neurodegeneration, large efforts have gone into developing treatments to reduce Aβ aggregation and remove Aβ plaques. These treatments include the related antibodies , which has been granted accelerated FDA approval, along with , , , , and , which are at varying stages of clinical development. Despite the clear association of Aβ aggregation with AD, treatments aimed at preventing Aβ aggregation or removing pre-existing Aβ plaques have shown little to no clinical benefit thus far and remain controversial. Gantenerumab is a fully human IgG1κ monoclonal antibody derived from the MorphoSys HuCAL®-Fab1 phage display library and subsequently optimized by _in vitro_ CDR cassette exchange. Gantenerumab binds to a unique Aβ epitope compared to other anti-Aβ antibodies and preferentially recognizes Aβ oligomers and fibrils over monomers.

Absorption:

The absorption characteristics of Gantenerumab are crucial for its therapeutic efficacy: Gantenerumab administered as a single 300 mg subcutaneous injection in healthy volunteers over five or 15 seconds yielded a median T_max of 119 hours (roughly five days). Only ~1% of administered gantenerumab crosses the blood-brain barrier, such that at 1200 mg doses given subcutaneously, peak brain steady-state exposure is reached in approximately five months. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Gantenerumab is an important consideration for its dosing schedule: Gantenerumab administered as a single 300 mg subcutaneous injection in healthy volunteers over five or 15 seconds yielded a mean half-life of 22 or 21 days, respectively. This determines the duration of action and helps in formulating effective dosing regimens.

Pharmacodynamics:

Gantenerumab exerts its therapeutic effects through: Positron emission tomography (PET) studies of Alzheimer's patients receiving subcutaneous gantenerumab up to 1200 mg every four weeks confirmed the ability of gantenerumab to reduce amyloid plaque burden to at or near the amyloid positivity threshold (80% of patients below this threshold after 36 months of treatment). The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Gantenerumab functions by: 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 (K_D 1.2 nM, k_d 4.9 x 10^-4 s^-1) and fibrils (K_D 0.6 nM, k_d 2.8 x 10^-4 s^-1) with less stable binding to monomers (K_D 17 nM, k_d 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. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Classification:

Gantenerumab belongs to the None, classified under the direct parent group Peptides. This compound is a part of the Organic Compounds, falling under the Organic Acids superclass, and categorized within the Carboxylic Acids and Derivatives class, specifically within the Amino Acids, Peptides, and Analogues subclass.

Categories:

Gantenerumab is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Blood Proteins, Globulins, Immunoglobulins, Immunoproteins, Proteins, Serum Globulins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.