Biosimilars: initial excitement gives way to reality

Belsey, Mark J.; Harris, Laura M.; Das, Romita R.; Chertkow, Joanna

doi:10.1038/nrd2093

Cited by 27 publications

(17 citation statements)

References 5 publications

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“…63,64 To provide a process for the approval of generic biologics, it is becoming clear that legislative action will be required. 65 Senators Hillary Rodham Clinton (D-NY) and Charles Schumer (D-NY) and Representative Henry Waxman (D-CA) introduced a bill (HR 6257) on September 29, 2006, seeking to expand access to lowercost generic versions of biotechnology medications. The bill would provide guidance to FDA on the review and approval of follow-on products using standards analogous to those used to approve conventional generic drugs (similarity of molecular structure and action), empower pharmacists to make generic substitution of approved products, and provide tax incentives to manufacturers to develop generic biologics.…”

Section: Generic Drugsmentioning

confidence: 99%

Projecting future drug expenditures—2007

Hoffman

Shah

Vermeulen

et al. 2007

American Journal of Health-System Pharmacy

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Section: Generic Drugsmentioning

confidence: 99%

Projecting future drug expenditures—2007

Hoffman

Shah

Vermeulen

et al. 2007

American Journal of Health-System Pharmacy

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“…Therapeutic proteins now represent a significant segment of the pharmaceutical industry [1] and include some of the most innovative products which are on the cutting edge of clinical care. This class of therapeutics is clearly different from small molecule synthetic drugs.…”

Section: Introductionmentioning

confidence: 99%

Aptamers as a Sensitive Tool to Detect Subtle Modifications in Therapeutic Proteins

et al. 2012

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Therapeutic proteins are derived from complex expression/production systems, which can result in minor conformational changes due to preferential codon usage in different organisms, post-translational modifications, etc. Subtle conformational differences are often undetectable by bioanalytical methods but can sometimes profoundly impact the safety, efficacy and stability of products. Numerous bioanalytical methods exist to characterize the primary structure of proteins, post translational modifications; protein-substrate/protein/protein interactions and functional bioassays are available for most proteins that are developed as products. There are however few analytical techniques to detect changes in the tertiary structure of proteins suitable for use during drug development and quality control. For example, x-ray crystallography and NMR are impractical for routine use and do not capture the heterogeneity of the product. Conformation-sensitive antibodies can be used to map proteins. However the development of antibodies to represent sufficient epitopes can be challenging. Other limitations of antibodies include limited supply, high costs, heterogeneity and batch to batch variations in titer. Here we provide proof-of-principle that DNA aptamers to thrombin can be used as surrogate antibodies to characterize conformational changes. We show that aptamers can be used in assays using either an ELISA or a label-free platform to characterize different thrombin products. In addition we replicated a heat-treatment procedure that has previously been shown to not affect protein activity but can result in conformational changes that have serious adverse consequences. We demonstrate that a panel of aptamers (but not an antibody) can detect changes in the proteins even when specific activity is unaffected. Our results indicate a novel approach to monitor even small changes in the conformation of proteins which can be used in a routine drug-development and quality control setting. The technique can provide an early warning of structural changes during the manufacturing process that could have consequential outcomes downstream.

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“…Biosimilars are defined as biological medicinal products comparable (but not necessarily identical) in quality, efficacy and safety to reference products. 3 These qualities have captured the interest of drug companies that are focused on developing less expensive biosimilar antibodies and derivatives, such as TNFR-Ig, VEGFR-Ig, CTLA4-Ig, and PDL1-Ig. To expedite the development of biosimilars in Europe, the European Medicines Agency (EMA) has established a series of guidelines.…”

Section: Introductionmentioning

confidence: 99%

Versatile characterization of glycosylation modification in CTLA4-Ig fusion proteins by liquid chromatography-mass spectrometry

Zhu

Guo

Guo³

et al. 2014

mAbs

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These authors contributed equally to this work.Keywords: characterization, CTLA4-Ig fusion protein, glycan, glycosylation modification, intact protein, mass spectrometry, peptide mapping, similarity CTLA4-Ig is a highly glycosylated therapeutic fusion protein that contains multiple N-and O-glycosylation sites. Glycosylation plays a vital role in protein solubility, stability, serum half-life, activity, and immunogenicity. For a CTLA4-Ig biosimilar development program, comparative analytical data, especially the glycosylation data, can influence decisions about the type and amount of animal and clinical data needed to establish biosimilarity. Because of the limited clinical experience with biosimilars before approval, a comprehensive level of knowledge about the biosimilar candidates is needed to achieve subsequent development. Liquid chromatography-mass spectrometry (LC-MS) is a versatile technique for characterizing N-and O-glycosylation modification of recombinant therapeutic proteins, including 3 levels: intact protein analysis, peptide mapping analysis, and released glycans analysis. In this report, an in-depth characterization of glycosylation of a candidate biosimilar was carried out using a systematic approach: N-and O-linked glycans were identified and electron-transfer dissociation was then used to pinpoint the 4 occupied O-glycosylation sites for the first time. As the results show, the approach provides a set of routine tools that combine accurate intact mass measurement, peptide mapping, and released glycan profiling. This approach can be used to comprehensively research a candidate biosimilar Fc-fusion protein and provides a basis for future studies addressing the similarity of CTLA4-Ig biosimilars.

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Biosimilars: initial excitement gives way to reality

Cited by 27 publications

References 5 publications

Projecting future drug expenditures—2007

Projecting future drug expenditures—2007

Aptamers as a Sensitive Tool to Detect Subtle Modifications in Therapeutic Proteins

Versatile characterization of glycosylation modification in CTLA4-Ig fusion proteins by liquid chromatography-mass spectrometry

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