Gantenerumab

This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.

Identification

Summary

Gantenerumab is a fully human IgG1κ monoclonal antibody with specificity for amyloid-beta oligomers and fibrils under investigation for the treatment of Alzheimer's disease.

Generic Name
Gantenerumab
DrugBank Accession Number
DB12034
Background

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.1,2 These treatments include the related antibodies aducanumab, which has been granted accelerated FDA approval, along with bapineuzumab, crenezumab, donanemab, lecanemab, and solanezumab, 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.1,2,9

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.4

Type
Biotech
Groups
Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
Not Available
Protein Average Weight
Not Available
Sequences
Not Available
Synonyms
  • Gantenerumab

Pharmacology

Indication

Not Available

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Pharmacodynamics

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).6,7

Mechanism of action

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.1,2

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.1,2,3 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.2 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.1 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.2

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).4 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.4,5

TargetActionsOrganism
AAmyloid beta A4 protein
antagonist
binder
antibody
Humans
Absorption

Gantenerumab administered as a single 300 mg subcutaneous injection in healthy volunteers over five or 15 seconds yielded a median Tmax of 119 hours (roughly five days).8 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.9

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

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.8

Clearance

Not Available

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Gantenerumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Gantenerumab.
AducanumabThe risk or severity of adverse effects can be increased when Gantenerumab is combined with Aducanumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Gantenerumab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Gantenerumab.
Food Interactions
Not Available

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
4DF060P933
CAS number
1043556-46-2

References

General References
  1. Roda AR, Serra-Mir G, Montoliu-Gaya L, Tiessler L, Villegas S: Amyloid-beta peptide and tau protein crosstalk in Alzheimer's disease. Neural Regen Res. 2022 Aug;17(8):1666-1674. doi: 10.4103/1673-5374.332127. [Article]
  2. Decourt B, Boumelhem F, Pope ED 3rd, Shi J, Mari Z, Sabbagh MN: Critical Appraisal of Amyloid Lowering Agents in AD. Curr Neurol Neurosci Rep. 2021 Jun 10;21(8):39. doi: 10.1007/s11910-021-01125-y. [Article]
  3. Torres AK, Rivera BI, Polanco CM, Jara C, Tapia-Rojas C: Phosphorylated tau as a toxic agent in synaptic mitochondria: implications in aging and Alzheimer's disease. Neural Regen Res. 2022 Aug;17(8):1645-1651. doi: 10.4103/1673-5374.332125. [Article]
  4. Bohrmann B, Baumann K, Benz J, Gerber F, Huber W, Knoflach F, Messer J, Oroszlan K, Rauchenberger R, Richter WF, Rothe C, Urban M, Bardroff M, Winter M, Nordstedt C, Loetscher H: Gantenerumab: a novel human anti-Abeta antibody demonstrates sustained cerebral amyloid-beta binding and elicits cell-mediated removal of human amyloid-beta. J Alzheimers Dis. 2012;28(1):49-69. doi: 10.3233/JAD-2011-110977. [Article]
  5. Ostrowitzki S, Deptula D, Thurfjell L, Barkhof F, Bohrmann B, Brooks DJ, Klunk WE, Ashford E, Yoo K, Xu ZX, Loetscher H, Santarelli L: Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol. 2012 Feb;69(2):198-207. doi: 10.1001/archneurol.2011.1538. Epub 2011 Oct 10. [Article]
  6. Klein G, Delmar P, Voyle N, Rehal S, Hofmann C, Abi-Saab D, Andjelkovic M, Ristic S, Wang G, Bateman R, Kerchner GA, Baudler M, Fontoura P, Doody R: Gantenerumab reduces amyloid-beta plaques in patients with prodromal to moderate Alzheimer's disease: a PET substudy interim analysis. Alzheimers Res Ther. 2019 Dec 12;11(1):101. doi: 10.1186/s13195-019-0559-z. [Article]
  7. Klein G, Delmar P, Kerchner GA, Hofmann C, Abi-Saab D, Davis A, Voyle N, Baudler M, Fontoura P, Doody R: Thirty-Six-Month Amyloid Positron Emission Tomography Results Show Continued Reduction in Amyloid Burden with Subcutaneous Gantenerumab. J Prev Alzheimers Dis. 2021;8(1):3-6. doi: 10.14283/jpad.2020.68. [Article]
  8. Portron A, Jordan P, Draper K, Muenzer C, Dickerson D, van Iersel T, Hofmann C: A Phase I Study to Assess the Effect of Speed of Injection on Pain, Tolerability, and Pharmacokinetics After High-volume Subcutaneous Administration of Gantenerumab in Healthy Volunteers. Clin Ther. 2020 Jan;42(1):108-120.e1. doi: 10.1016/j.clinthera.2019.11.015. Epub 2019 Dec 26. [Article]
  9. Tolar M, Abushakra S, Hey JA, Porsteinsson A, Sabbagh M: Aducanumab, gantenerumab, BAN2401, and ALZ-801-the first wave of amyloid-targeting drugs for Alzheimer's disease with potential for near term approval. Alzheimers Res Ther. 2020 Aug 12;12(1):95. doi: 10.1186/s13195-020-00663-w. [Article]
PubChem Substance
347911273
Wikipedia
Gantenerumab

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentAlzheimer's Disease (AD)2
3TerminatedTreatmentAlzheimer's Disease (AD)5
2TerminatedTreatmentAlzheimer's Disease (AD)1
2, 3CompletedTreatmentAlzheimer's Disease (AD) / Dementia / Familial Alzheimer Disease (FAD)1
2, 3RecruitingTreatmentAlzheimer's Disease (AD) / Dementia / Familial Alzheimer Disease (FAD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
Binder
Antibody
General Function
Transition metal ion binding
Specific Function
Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and tra...
Gene Name
APP
Uniprot ID
P05067
Uniprot Name
Amyloid beta A4 protein
Molecular Weight
86942.715 Da
References
  1. Bohrmann B, Baumann K, Benz J, Gerber F, Huber W, Knoflach F, Messer J, Oroszlan K, Rauchenberger R, Richter WF, Rothe C, Urban M, Bardroff M, Winter M, Nordstedt C, Loetscher H: Gantenerumab: a novel human anti-Abeta antibody demonstrates sustained cerebral amyloid-beta binding and elicits cell-mediated removal of human amyloid-beta. J Alzheimers Dis. 2012;28(1):49-69. doi: 10.3233/JAD-2011-110977. [Article]
  2. Ostrowitzki S, Deptula D, Thurfjell L, Barkhof F, Bohrmann B, Brooks DJ, Klunk WE, Ashford E, Yoo K, Xu ZX, Loetscher H, Santarelli L: Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol. 2012 Feb;69(2):198-207. doi: 10.1001/archneurol.2011.1538. Epub 2011 Oct 10. [Article]

Drug created at October 20, 2016 21:13 / Updated at January 22, 2022 00:13