Therapeutic Monoclonal Antibodies Approved by FDA in 2016

Cai, Henry Hongrong

doi:10.15406/moji.2016.05.00145

Cited by 6 publications

(6 citation statements)

References 1 publication

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“…Monoclonal antibody (mAb) drugs are in the mainstream of clinical practice for treatment of a range of diseases, with cancers and autoimmune disorders being the most common targets. As of January 11, 2017, 68 mAb drug products have been approved by the U.S. Food and Drug Administration (FDA), 1 and more are in clinical trials 2 or being developed as biosimilars. The inherent heterogeneity of mAb glycosylation is one complex aspect of mAb drugs that is important for their safety and efficacy.…”

Section: Graphical Abstractmentioning

confidence: 99%

Chemical Structure and Composition of Major Glycans Covalently Linked to Therapeutic Monoclonal Antibodies by Middle-Down Nuclear Magnetic Resonance

et al. 2018

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Glycosylation of monoclonal antibodies (mAbs) is a critical quality attribute that can impact mAb drug efficacy and safety. The mAb glycans are inherently heterogeneous in chemical structure and composition of monosaccharides. The established fluorescence or mass-spectrometry (MS) detection methods for glycosylation evaluation may require multiple steps of glycan cleavage or extensive digestion of the mAb, chemical labeling of the glycans, column separation and report the chemical identity of glycans indirectly through retention time and molecular weight values. In demonstrating chemical structure similarity and comparability among mAb drugs, orthogonal analytical methods for measuring glycan chemistry are needed to ensure the quality of drug products. Here, a "middle-down" NMR method is developed as a proof-of-concept approach to measure the domain-specific glycosylation of marketed mAb drugs without cleavage of the glycan moieties. Complete glycan H/C chemical shift assignments were obtained at C natural abundance from commercial standard glycans that allowed unambiguous determination of the chemical structure, glycosidic linkage position, and anomeric configuration of each monosaccharide in the major N-glycan scaffolds found in mAb molecules. The analysis of glycan anomeric peaks in two-dimensional (2D)H-C NMR spectra yielded metrics for clinically important mAb quality attributes (i.e., galactosylation (Gal%) and fucosylation (Fuc%)), consistent with literature results using a standard glycan-mapping method. Therefore, the middle-down NMR method provided a facile orthogonal measurement for mAb glycosylation characterization with improved chemical information content on glycan structure determination and quantification, compared to standard approaches.

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Section: Graphical Abstractmentioning

confidence: 99%

Chemical Structure and Composition of Major Glycans Covalently Linked to Therapeutic Monoclonal Antibodies by Middle-Down Nuclear Magnetic Resonance

et al. 2018

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“…Monoclonal antibodies (mAbs) are a major class of protein therapeutics in drug development pipelines and in the biopharmaceutical drug market. To date, more than 60 mAbs have been approved for treating diseases in several therapeutic areas in the US ( 1 ). Currently, there are more than 50 mAbs in late-stage clinical studies and many more in early stages of development ( 2 , 3 ).…”

Section: Introductionmentioning

confidence: 99%

Impact of Tryptophan Oxidation in Complementarity-Determining Regions of Two Monoclonal Antibodies on Structure-Function Characterized by Hydrogen-Deuterium Exchange Mass Spectrometry and Surface Plasmon Resonance

et al. 2018

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PurposeTryptophan’s (Trp) unique hydrophobic and structural properties make it an important antigen binding motif when positioned in complementarity-determining regions (CDRs) of monoclonal antibodies (mAbs). Oxidation of Trp residues within the CDR can deleteriously impact antigen binding, particularly if the CDR conformation is altered. The goal of this study was to evaluate the conformational and functional impact of Trp oxidation for two mAb subtypes, which is essential in determining the structure-function relationship and establishing appropriate analytical control strategies during protein therapeutics development.MethodsSelective Trp oxidation was induced by 2,2′-Azobis(2-amidinopropane) dihydrochloride (AAPH) treatment in the presence of free methionine (Met). The native and chemically oxidized mAbs were characterized by hydrogen-deuterium exchange mass spectrometry (HDX-MS) for conformational changes and surface plasmon resonance (SPR) for antigen-antibody binding.ResultsTreatment of mAbs with AAPH selectively oxidized solvent accessible Trp residues. Oxidation of Trp within or in proximity of CDRs increased conformational flexibility in variable domains and disrupted antigen binding.ConclusionsTrp oxidation in CDRs can adversely impact mAbs’ conformation and antigen binding. Trp oxidation should be carefully evaluated as part of critical quality attribute assessments. Oxidation susceptible Trp should be closely monitored during process development for mAbs to establish appropriate analytical control for manufacturing of drug substance and drug product.Electronic supplementary materialThe online version of this article (10.1007/s11095-018-2545-8) contains supplementary material, which is available to authorized users.

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“…Since the breakthrough of monoclonal antibody (mAb) production using hybridoma cell culture in 1975, mAbs have become one of the major targets for drug discovery [ 21 ]. As of 2017, approximately 70 mAbs have been approved by the United States Food and Drug Administration (FDA) for treating a variety of human diseases including cancers, chronic inflammatory diseases, infectious diseases and neurodegenerative diseases [ 22 ].…”

Section: Monoclonal Antibody As Therapymentioning

confidence: 99%

Development of Antibody Therapeutics against Flaviviruses

Sun

Chen

Lai

2017

IJMS

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Recent outbreaks of Zika virus (ZIKV) highlight the urgent need to develop efficacious interventions against flaviviruses, many of which cause devastating epidemics around the world. Monoclonal antibodies (mAb) have been at the forefront of treatment for cancer and a wide array of other diseases due to their specificity and potency. While mammalian cell-produced mAbs have shown promise as therapeutic candidates against several flaviviruses, their eventual approval for human application still faces several challenges including their potential risk of predisposing treated patients to more severe secondary infection by a heterologous flavivirus through antibody-dependent enhancement (ADE). The high cost associated with mAb production in mammalian cell cultures also poses a challenge for the feasible application of these drugs to the developing world where the majority of flavivirus infection occurs. Here, we review the current therapeutic mAb candidates against various flaviviruses including West Nile (WNV), Dengue virus (DENV), and ZIKV. The progress of using plants for developing safer and more economical mAb therapeutics against flaviviruses is discussed within the context of their expression, characterization, downstream processing, neutralization, and in vivo efficacy. The progress of using plant glycoengineering to address ADE, the major impediment of flavivirus therapeutic development, is highlighted. These advancements suggest that plant-based systems are excellent alternatives for addressing the remaining challenges of mAb therapeutic development against flavivirus and may facilitate the eventual commercialization of these drug candidates.

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Therapeutic Monoclonal Antibodies Approved by FDA in 2016

Cited by 6 publications

References 1 publication

Chemical Structure and Composition of Major Glycans Covalently Linked to Therapeutic Monoclonal Antibodies by Middle-Down Nuclear Magnetic Resonance

Chemical Structure and Composition of Major Glycans Covalently Linked to Therapeutic Monoclonal Antibodies by Middle-Down Nuclear Magnetic Resonance

Impact of Tryptophan Oxidation in Complementarity-Determining Regions of Two Monoclonal Antibodies on Structure-Function Characterized by Hydrogen-Deuterium Exchange Mass Spectrometry and Surface Plasmon Resonance

Development of Antibody Therapeutics against Flaviviruses

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