NMR spots biosimilars: Filgrastim found

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  • Published: Feb 15, 2016
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: NMR spots biosimilars: Filgrastim found

Differently similar

Granulocyte colony-stimulating factor (GCSF), a protein consisting of about 175 amino acids (colors), stimulates the bone marrow to produce neutrophils, a type of white blood cell. Filgrastim (Methionine-GCSF) is the recombinant DNA analog of GCSF. It is used to ward off infection and anemia in cancer patients. (Credit: Protein Data Bank)

Protein NMR spectroscopy can be used to demonstrate the high similarity of the three dimensional structure between various product sources according to research published in the journal Nature Biotechnology.

Protein therapeutics manufactured from living cells can look almost the same, which can be a problem for biotechnology and pharmaceutical companies hoping to patent and market such products. Moreover, it makes regulating these agents difficult too. However, two-dimensional nuclear magnetic resonance spectroscopy(2D NMR), "can be a robust and powerful complementary technique for companies and regulators" when assessing biosimilars, according to research chemist Robert Brinson of the National Institute of Standards and Technology (NIST). Brinson and his colleagues recognise that this spectroscopic assessment could be part of a set of comparisons required to determine whether a biosimilar product is so similar to an existing product as to suggest that there is no "clinically meaningful" difference between the two.

Approving look

"Other analytical methods provide useful information, but 2D NMR is one of the few approaches that can yield complete assignment of three-dimensional structure across the entire molecule in solution at atomic-level resolution," Brinson explains. "Our study indicates that 2D NMR data can yield a precise and unique 'fingerprint' of structural information in a biological product," he adds. In terms of research and regulation, unlike chemically synthesized small molecule drugs, biologically produced protein-type agents are not necessarily identical from batch to batch. Nevertheless, they have to be demonstrated as being close enough to the approved version in terms of activity and any side-effects to be licensed.

Brinson and his colleagues analysed four independently manufactured versions of filgrastim, a biological drug used to help ward off infection and anaemia in cancer patients. At four different laboratories, scientists used 2D NMR to map the atomic structures of the original, reference, filgrastim licensed in the US and compared the spectra to those from three unapproved biosimilar versions. The US Food and Drug Administration (FDA) defines a biosimilar, as a biological product shown to be "highly similar to an FDA-approved biological product, and has no clinically meaningful differences in terms of safety and effectiveness." Only minor differences in clinically inactive components are allowable in biosimilar products. Biosimilar versions of approved biological drugs at the end of their patent life are expected to cost less but be as safe and effective for licensed clinical uses. To date, the FDA has approved one biosimilar (a version of filgrastim), while the European Union has approved about 20 biosimilars over the last 10 years.

Filgrastim

Samples of the four filgrastim products were measured on six NMR instruments made by two manufacturers and distributed across laboratories at NIST, FDA’s Center for Drug Evaluation and Research, the Medical Products Agency of Sweden, and Health Canada’s Center for Biologics Evaluation. Statistical analysis of the spectra revealed how closely the spectral lines matched. The same spectra were also recorded a year later to test stability. The experimentally determined precision limit of 8 parts per billion for the interlaboratory comparison, the researchers write, is 'well below' the threshold beyond which structural differences due to mutations, changes in three-dimensional structure, or other causes might be obscured.

In the next phase of the work, Brinson says, NIST and collaborators will harmonise 2D NMR measurement protocols for monoclonal antibody (mAb) therapeutics using a mAb that NIST is developing as a reference material. Monoclonal antibodies are the largest class of approved protein therapeutics and perhaps the most well known. the ability to use 2D NMR with monoclonal antibodies would be an important step forward in their characterization for research and regulation purposes.

"The next step is the harmonization of measurement protocols and statistical analyses for the structural assessment of monoclonal antibody therapeutics," Brinson told SpectroscopyNOW. "The Nature Biotech paper represented a pilot interlaboratory study with three regulatory agencies and NIST - we are a non-regulatory agency. The next phase involves a consortium of approximately 30 global partners from ten countries, with nearly equal participation from industry, academia, government agencies, and instrument vendors."

Related Links

Nature Biotechnol 2016, online: "Precision and Robustness of 2D NMR for Structure Assessment of Filgrastim Biosimilars"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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