Monoclonal antibody therapeutics: history and future

Buss, Nicholas; Henderson, Simon J.; McFarlane, Mary; Shenton, Jacintha; Haan, Lolke de

doi:10.1016/j.coph.2012.08.001

Cited by 368 publications

(271 citation statements)

References 55 publications

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“…However, target specificity, reduced off-target side effects, and better pharmacokinetics make antibody and protein therapeutics an attractive and promising approach for targeting CNS diseases [2,3]. Furthermore, progress in the field of Alzheimer's passive immunotherapy-particularly results showing that peripherally administered beta amyloid (Aβ) antibodies can cross the BBB and reduce amyloid plaque-have spurred efforts to raise antibodies to other CNS targets [4].…”

Section: Introductionmentioning

confidence: 99%

Developing Therapeutic Antibodies for Neurodegenerative Disease

Yu¹,

Watts²

2013

Neurotherapeutics

180

171

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The central nervous system has been considered off-limits to antibody therapeutics. However, recent advances in preclinical and clinical drug development suggest that antibodies can cross the blood-brain barrier in limited quantities and act centrally to mediate their effects. In particular, immunotherapy for Alzheimer's disease has shown that targeting beta amyloid with antibodies can reduce pathology in both mouse models and the human brain, with strong evidence supporting a central mechanism of action. These findings have fueled substantial efforts to raise antibodies against other central nervous system targets, particularly neurodegenerative targets, such as tau, beta-secretase, and alpha-synuclein. Nevertheless, it is also apparent that antibody penetration across the blood-brain barrier is limited, with an estimated 0.1-0.2 % of circulating antibodies found in brain at steady-state concentrations. Thus, technologies designed to improve antibody uptake in brain are receiving increased attention and are likely going to represent the future of antibody therapy for neurologic diseases, if proven safe and effective. Herein we review briefly the progress and limitations of traditional antibody drug development for neurodegenerative diseases, with a focus on passive immunotherapy. We also take a more in-depth look at new technologies for improved delivery of antibodies to the brain.

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Section: Introductionmentioning

confidence: 99%

Developing Therapeutic Antibodies for Neurodegenerative Disease

Yu¹,

Watts²

2013

Neurotherapeutics

180

171

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“…Since their introduction in the late 1980s, therapeutic mAbs have become very popular drug candidates due to this high specificity and low toxicity. At present, approximately 30 mAbs are used for human therapeutics for oncology, autoimmunity, inflammation, infectious diseases, and metabolic disorders [7,8]. Most of the clinically approved mAbs are IgG1s, which are composed of two heavy chains (50 kDa each) and two light chains (25 kDa each) covalently linked by disulfide bridges.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive glycosylation profiling of IgG and IgG-fusion proteins by top-down MS with multiple fragmentation techniques

Tran

Barton²,

Feng³

et al. 2016

Journal of Proteomics

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We employed top-and middle-down analyses with multiple fragmentation techniques including electron transfer dissociation (ETD), electron capture dissociation (ECD), and matrix-assisted laser desorption ionization in-source decay (MALDI-ISD) for characterization of a reference monoclonal antibody (mAb) IgG1 and a fusion IgG protein. Fourier transform ion cyclotron resonance (FT-ICR) or high performance liquid chromatography electrospray ionization (HPLC-ESI) on an Orbitrap was employed. These experiments provided a comprehensive view on the protein species; especially for different glycosylation level in these two proteins, which showed good agreement with oligosaccharide profiling. Top-and middle-down MS provided additional information regarding glycosylation sites and different combinational protein species that were not available from oligosaccharide mapping or conventional bottom-up analysis. Finally, incorporating a limited enzymatic digestion by immunoglobulin G-degrading enzyme of Streptococcus pyogene (IdeS) with MALDI-ISD analysis enabled extended sequence coverage of the internal region of protein without pre-fractionation. Biological significance: Oligosaccharide profiling together with top-and middle-down methods enabled: 1) detection of heterogeneous glycosylated protein species and sites in intact IgG1 and fusion proteins with high mass accuracy, 2) estimation of relative abundance levels of protein species in the sample, 3) confirmation of the protein termini structural information, and 4) improved sequence coverage by MALDI-ISD analysis for the internal regions of the proteins without sample pre-fractionation.

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“…18,19 As of early 2015, nearly 50 mAb products were approved or were under regulatory review in either the US or EU, and others are being developed for various indications. 20 Although the typical pharmacological doses of mAbs comprise tens or hundreds of mg, some therapeutic agents require substantially lower doses.…”

Section: Introductionmentioning

confidence: 99%

Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration

Morar-Mitrica

Puri

Sassi

et al. 2015

mAbs

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The physical and chemical integrity of a biopharmaceutical must be maintained not only during long-term storage but also during administration. Specifically for the intravenous (i.v.) delivery of a protein drug, loss of stability can occur when the protein formulation is compounded with i.v. bag diluents, thus modifying the original composition of the drug product. Here we present the challenges associated with the delivery of a low-dose, highly potent monoclonal antibody (mAb) via the i.v. route. Through parallel in-use stability studies and conventional formulation development, a drug product was developed in which adsorptive losses and critical oxidative degradation pathways were effectively controlled. This development approach enabled the i.v. administration of clinical doses in the range of 0.1 to 0.5 mg total protein, while ensuring liquid drug product storage stability under refrigerated conditions.

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Monoclonal antibody therapeutics: history and future

Cited by 368 publications

References 55 publications

Developing Therapeutic Antibodies for Neurodegenerative Disease

Developing Therapeutic Antibodies for Neurodegenerative Disease

Comprehensive glycosylation profiling of IgG and IgG-fusion proteins by top-down MS with multiple fragmentation techniques

Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration

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