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In vivo Functional Formulation Monoclonal Antibodies and Recombinant Proteins

November 6th, 2008 by Wm. Pat Leinert

It’s a privilege to introduce myself to life scientists through our new biotechnology blog. My name is Wm. Patrick Leinert and I’m the CEO of Leinco Technologies, a global biosciences company founded in 1992. The primary objective of this blog is to initiate a meaningful dialogue that will allow me to share with you my professional experiences and also learn from yours.  I’m the founder of two successful biotechnology companies, both have been highly focused on proteomics.  My scientific interests and passions are in the life sciences with over 25 years of experience in cell line development, mammalian cell culture, protein expression, purification, modification of proteins and most recently I have filed a patent on a novel transgene protein expression system. 

 

I would like to suggest that world class scientists conducting In vivo and In vitro functional research with monoclonal antibodies and recombinant proteins consider purity specifications as important criteria for selecting a suitable  protein reagent. It’s my opinion that researchers do not have readily available at their disposal, monoclonal antibodies and recombinant proteins that meet the purity levels required to generate reliable data from functional research studies.  I believe such data is desired by world class scientists, whether conducting basic life science research or for development of protein therapeutics.

 

Through our close collaborations with you, our academic and corporate partners, we have determined that certain critical purity specifications should be considered for validation of authentic functional formulation antibodies and recombinant proteins. Important purity specifications for functional applications include minimization or complete removal of antibody aggregates, endotoxins, leached protein A, DNA, RNA, and the selection of a final formulation buffer that is neutral to physiological functions within test animals and stabilizes the protein’s biological activity and format.

 

There are nearly 200 monoclonal antibodies (constituting 20% of the protein therapeutics) in human clinical trials. 1

A robust purification process is required to achieve homogenous monomeric monoclonal antibody preparations. For monoclonal antibodies, it is important to develop a final buffer formulation and storage conditions that maintain the original monomeric form of the protein following purification.  Potential effects of antibody aggregates include hypersensitivity or anaphylaxis, changes in biological activity, organ failure, activation of cellular receptors intending to neutralize and diminished overall efficacy of the antibody. 

 

Antibodies can undergo covalent and non-covalent associations that are highly dependent on formulation including pH, ionic strength and excipients. 1 Multiple intra-domain and inter-domain linkages can lead to disulfide bonds causing heterogeneity and aggregation. 1 Based on our extensive development and manufacturing experience, I would like to suggest that the following factors affecting aggregation be studied to assure stability of your antibody for functional applications at a very early stage: protein structure, freeze rates, storage temperature, freeze thaw cycles, storage containers, size of containers, buffer formulation, pH and photo stability.

 

Endotoxins are complex bacterial toxins composed of proteins, lipids, and polysaccharides, which are released upon lyses of gram negative (-) bacteria that may have entered the manufacturing process. Endotoxins, also called lipopolysaccharides (LPS), are major contaminants found in commercially available proteins, antibodies or biologically active substances, which often complicate study of the biological effects of the main protein ingredient. The presence of small amounts of endotoxin in recombinant proteins and antibody preparations can cause side effects in host animals such as endotoxin shock, tissue injury, and even death. Due to these reactions, it is essential to remove endotoxins from drugs, injectables, and other biological and pharmaceutical products.  In conclusion, endotoxin levels must be considered when developing potential protein therapeutics, conducting preclinical trials and manufacturing medical devices that come in contact with blood, lymph or cerebrospinal fluid. 2, 3, 4

The presence of Protein A in preclinical or therapeutic monoclonal antibody preparations due to leaching during Protein A chromatography has been linked with toxicity, anaphylaxis, antibody aggregation and interference with immunoassays in host animals and humans.  Sensitive ELISA assays have been developed to detect sub nanogram levels of leached protein A. 5, 6  Purification procedures must be developed to minimize protein A leaching. Considerations such as temperature, column washing and matrix regeneration should be considered to reduce protein A contamination to levels < 10 ng/mg of antibody.  

 

We typically use a two step chromatography method to remove trace amounts of genomic DNA and RNA to assure purity criteria is met for In vivo functional formulation monoclonal antibodies.  Once the purification method is established, formulation screening is initiated early in the development phase before establishing the dose for animals.  Formulation is an important factor to eliminate degradation from monomer to aggregates especially when protein concentrations are often high due to dosage requirements.   

 

1. Addressing Stability of Biological Drugs. Genetic Engineering & Biotechnology News. Vol. 25, No. 6 Mar 15, 2005

2. Transfusion and Infusion Assemblies and Similar Medical Devices. Chapter <161>. USP 31, p. 124. United States Pharmacopeial Convention. Rockville, MD, 2007.

3. Bacterial Endotoxins Test. Chapter <85>. USP 31, pp. 98-102. United States Pharmacopeial Convention, Rockville, MD, 2007.

4. Methods of Endotoxin Removal from Biological Preparations a Review.  J Pharm Pharmaceut Sci 10 (3): 388-404, 2007 

5. The measurement of staphylococcal protein A by ELISA in immunoglobulin preparations. Biologicals Oct, 19 (4) 271-279, 1991

6.  Purification and Analysis of Recombinant Proteins a Book. By Ramnath Seetharam, Satish K. Sharma Science 321 Pages 1991

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