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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Analytical Proteomics as a Tool for the Characterization of Biologic Products and Discovery and Validation of Biomarkers

Principal Investigator: Michail A. Alterman, PhD
Office / Division / Lab: OCTGT / DCGT / TVBB


General Overview

The 21st Century will be a time of exciting new medical breakthroughs based on cellular, tissue, and gene therapies. These treatments hold great promise for improving our health and quality of life: they will enable physicians to treat certain diseases that are otherwise difficult or impossible to manage today. However, the complexity of these medical products poses major scientific and regulatory challenges to FDA regulators who are responsible for evaluating their safety and effectiveness. FDA is working to evaluate and develop the application of state-of-the-art analytical tools to fulfill this responsibility and ensure that safe and effective treatments are available to the public as quickly as possible.

My laboratory is evaluating and developing cutting-edge analytical tools for assessing the safety and effectiveness of cell, gene, and tissue therapies with regard to the manufacturing processes that produce them. We are particularly interested in developing ways to quickly, reliably, and precisely evaluate tell-tail signs of a product's potency, safety, and efficacy. Our strategy is to identify biomarkers that reflect these qualities in products. Biomarkers are molecules whose presence reflects specific states of activity, disease, response to drugs, potency, and other characteristics of cells and tissues. The use of appropriate biomarkers will enhance our ability to regulate complex biologic products and ensure that they are potent, safe, and effective.


Scientific Overview

Biologic medical products are very complex products derived from living sources that contain mixtures of proteins, carbohydrates, lipids and other biological molecules. My laboratory is looking for specific proteins in such products that might be useful biomarkers of safety, potency, and efficacy. As part of this effort we are developing ways to use a technique called mass-spectrometry (MS) proteomics. MS identifies molecules according to their mass, which is unique for each biological molecule; proteomics is the study of the types of protein present in cells and tissues at any particular moment during health, disease, or during medical treatments. We use MS proteomics to rapidly analyze complex mixtures of proteins and identify the individual components.

We also plan to test substrates--cell cultures that produce biologic products used to treat diseases. Substrates that are not designed or manufactured properly could yield products that are ineffective, unsafe, or both. The goal of this research program is to develop and adapt MS and proteomic techniques that can be used for qualitative and quantitative analytical testing of cells, cell-derived products and vaccines. Qualitative testing measures the characteristics of a product, such as its purity and ingredients; quantitative testing measures the amount of the actual biological therapeutic molecules. These tests are done to ensure products have been made properly and will work effectively. Specific projects:

1. Develop mass spectrometry-based analytical approaches for testing biological product quality and identity.

2. Develop a proteomics/MS-based approach to qualitative and quantitative testing of cell substrates and identification of potentially predictive biomarkers that might be able to be used to predict whether mesenchymal stem cells (cells that can change into a variety of different other cells) are safe and effective.

3. Develop a proteomics-based test that provides both qualitative and quantitative analysis for identity, potency and stability of influenza vaccine preparations.


Publications

Toxicol Appl Pharmacol 2013 Feb 15;267(1):125-36
Mass spectrometry-based proteomic analysis of human liver cytochrome(s) P450.
Shrivas K, Mindaye ST, Getie-Kebtie M, Alterman MA

J Proteomics 2013 Jan 14;78:1-14
Improved proteomic profiling of the cell surface of culture-expanded human bone marrow multipotent stromal cells.
Mindaye ST, Ra M, Losurdo J, Bauer S, Alterman MA

Anal Biochem 2011 Feb 15;409(2):202-12
Label-free mass spectrometry-based relative quantification of proteins separated by one-dimensional gel electrophoresis.
Getie-Kebtie M, Lazarev A, Eichelberger M, Alterman M

Food Chem 2010 Sep 1;122(1):314-8
Liquid-phase microextraction combined with gas chromatography mass spectrometry for rapid determination of nicotine in one-drop of nightshades vegetables and commercial food products
Shrivas K, Patel DK

Clin Chem 2010 Feb;56(2):165-71
Protein-based multiplex assays: mock presubmissions to the US Food and Drug Administration.
Regnier FE, Skates SJ, Mesri M, Rodriguez H, Tezak Z, Kondratovich MV, Alterman MA, Levin JD, Roscoe D, Reilly E, Callaghan J, Kelm K, Brown D, Philip R, Carr SA, Liebler DC, Fisher SJ, Tempst P, Hiltke T, Kessler LG, Kinsinger CR, Ransohoff DF, Mansfield E, Anderson NL

Proteomics Clin Appl 2009 Aug 1;3(8):979-88
Proteomics-based characterization of hemagglutinins in different strains of influenza virus.
Getie-Kebtie M, Chen D, Eichelberger M, Alterman M

J Proteome Res 2008 Sep;7(9):3697-707
Experimental evaluation of protein identification by an LC/MALDI/on-target digestion approach.
Getie-Kebtie M, Franke P, Aksamit R, Alterman MA

Toxicol In Vitro 2008 Apr;22(3):779-87
Utility of polyclonal antibodies targeted toward unique tryptic peptides in the proteomic analysis of cytochrome P450 isozymes.
Kornilayev BA, Alterman MA

Chem Res Toxicol 2007 Mar;20(3):511-9
A proteomic analysis of bromobenzene reactive metabolite targets in rat liver cytosol in vivo.
Koen YM, Gogichaeva NV, Alterman MA, Hanzlik RP

 

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