Sustainable Production of Plasma Proteins

Current methods for the extraction of plasma proteins have several limitations. Evolve Biologics is advancing a proprietary expanded bed chromatography solution that provides higher yields of high-quality proteins in a simpler, safer and more sustainable process that can be cost-effective at multiple scales.

Importance of Plasma Proteins

Many of the thousands of proteins found within human blood plasma have therapeutic value in treating a range of diseases, including immune deficiencies, autoimmune and neurological disorders and hemophilia, many of which are conside

red rare diseases.

The three most important plasma proteins from a market perspective include albumin, immunoglobulins (IgGs) and plasma-derived factor VIII. In 2017, immunoglobulin captured the leading position with more than 45% market share.1 Other plasma proteins of note include α1-antitrypsin (AAT), hyperimmune immunoglobulins, coagulation factors, fibrogammin and c1 esterase inhibitors (C1 INH).

The global market for therapeutic plasma proteins has grown significantly, increasing from approximately $5.8 billion in 2003 to over $21 billion in 2016 (excluding recombinant products).2 This strong growth has been driven in particular by greater diagnosis and expanded use in patients requiring treatments such as IgG, which includes the more recent introduction of subcutaneous IgG (SCIG), in addition to C1 INH and AAT.3 The global plasma market is expected to continue to grow in value terms to more than $31 billion at a CAGR of more than 7.5% through 2024,4

This future growth will be driven largely by the increasing demand for IgG for the treatment of patients for both new and existing indications, including primary immunodeficiency disorders (PIDs), in addition to continued geographic expansion.3 The global immunoglobulins market in 2016 was valued at over $10 billion for 2016, making up almost 50% of the global plasma market. The U.S. IgG market alone which accounts for over 40% of the global market in volume terms, is predicted to expand rapidly, growing at approximately 8% over the next five years.5

Demand for albumin is also expected to rise, owing to improved diagnosis of hypoalbuminemia caused by liver cirrhosis and hepatitis B, potential new indications and growing use in China,1 as well increasing use as a drug formulation agent, sealant in surgeries, vaccine ingredient and coating for medical devices.

History of Plasma Protein Production

Plasma proteins have traditionally been isolated from plasma using cold ethanol fractionation. Acid, alcohol and salts are employed at cold temperatures to precipitate proteins into fractions containing many proteins in their non-native forms. Specific proteins are purified by re-solubilizing the precipitated fractions. The method was initially developed in the 1940s by Harvard University professor Edwin Cohn to provide albumin for treatment of soldiers injured during World War II.

Limitations of Cold Fractionation

Cold ethanol fractionation was developed to extract albumin, not the 15–20 other proteins that have since been approved as therapeutics. Many of these other proteins are not stable in ethanol. In addition, ethanol is flammable and its storage, handling and use require extensive protective measures. Because the process is run at low temperature, it consumes significant energy and produces greenhouse gas emissions. As a result, cold fractionation presents significant safety and environmental issues.

Developing More Sustainable Technology

As Therapure Biopharma’s plasma products and technology division, Evolve Biologics is developing an alternative plasma protein production technique that eliminates the need for cold ethanol fractionation.

The company has been developing its proprietary PlasmaCap EBA® technology since 2012. PlasmaCap EBA uses proprietary affinity adsorbents in expanded bed adsorption (EBA) chromatography to capture plasma proteins directly from plasma without the use of precipitating solvents. The plasma is passed through a series of chromatography columns arranged in a particular sequence and designed to capture the proteins in their native form with a higher degree of efficiency and selectivity.

Each column contains dense, adsorbent, tungsten carbide beads coated with agarose modified with ligands designed to bind to a specific protein. The expanded bed columns provide more space between the beads than in traditional packed-bed chromatography, allowing the viscous plasma to flow through more quickly and without clogging.

A fluidizer rotates gently as the plasma passes through the column, generating optimal conditions for binding of the target protein and allowing the remaining proteins to flow through without any structural alterations. This design enables the extraction of more valuable proteins from each liter of donor plasma compared with legacy techniques.

Scalability for Modular Manufacturing

The expanded bed chromatography approach to plasma protein purification is also readily scalable. Due to its simplicity, it can be easily scaled up — and down. As a result, the technology enables economic operation at scales not typically employed by today’s cold ethanol fractionators.

With our PlasmaCap EBA technology, it is possible to construct small, modular facilities in countries and regions that collect smaller quantities of plasma (150,000–200,000 L annually). It is thought that dosing populations with indigenous proteins may lead to improved therapies, particularly for plasma proteins intended to treat immune diseases. The composition and quantity of IgG in plasma has been shown to vary greatly with the local environment and exposure to different infective agents. Domestic production of plasma proteins would also reduce the dependence of many countries on U.S.-derived plasma products.

Potential for Many New Plasma Protein Products

Although no new plasma proteins have been introduced in the major markets in last decade3, there are a number of products in clinical development, including plasminogen and reconstituted HDL.2 Several companies are also at the early stages of investigating the potential therapeutic effects of novel proteins not yet isolated from plasma. In addition, existing plasma proteins are under investigation for the treatment of expanded indications, such as IVIG for neurological diseases, AAT for type 1 diabetes, fibrinogen for aortic aneurysm surgery and C1 INH for antibody-mediated rejection in organ transplantation.3

Ambitious Goals for Evolve Biologics

Evolve has a three-pronged approach to the development and commercialization of human plasma proteins using our PlasmaCap EBA technology. Our first priority is commercialization of IVIG and albumin. IVIG is in the advanced stages of regulatory approval in Canada and the United States, having completed its phase III trial for PID in adults and with an ongoing phase III trial in pediatrics with regulatory submission expected in 2021. Regulatory submission is also expected for albumin in 2021. AAT is at the early development stage.

Once we have established a commercial facility for the manufacture of IVIG and albumin, growth will be driven by volume expansion, adding additional capacity to process larger volumes of plasma, complimented by geographic expansion utilizing a modular approach for countries that collect plasma domestically at volumes not generally addressed by those employing cold ethanol fractionation. 

We also believe that, having already innovated on the process for capturing plasma proteins, we now have the opportunity and the benefit of many years of hindsight to work with healthcare providers, patients and other market partners to innovate further to improve the way that these valuable plasma products are delivered and ultimately administered to the patient.

Finally, we plan on utilizing PlasmaCap EBA to mine the human proteome contained in our plasma for other proteins and build a robust pipeline. Evolve believes that our PlasmaCap EBA technology will provide enormous benefit to the industry and patients alike, not only by advancing the quality and reliable supply of plasma proteins, but also by enabling the cost-effective production of novel proteins present in small concentrations in human plasma.

Plasma is a scarce and valuable resource, one that in many countries is donated altruistically by their citizens. For me, this means that we have a m

oral obligation to provide the maximum therapeutic benefit we can from such a gift. In my opinion, a major obstacle to innovation is a focus on the solution as opposed to the problem. I have a great deal of admiration for professor Cohn and the process he developed — without a doubt, this was an outstanding solution for the problem at hand. However, I find it difficult to believe that anyone would argue that the challenge we face to today is the same one faced by professor Cohn more than 70 years ago. It is clear to most people I meet that the challenge facing the industry is no longer one focused on how to extract and purify a single protein (Albumin) but how to extract, purify and maintain the integrity of multiple proteins from a single liter of plasma. If we are to truly innovate, one must avoid becoming wedded to the solution and instead fall in love with the problem. At Evolve, we are seeking the best solution to a new problem, starting from a position with nothing invested and no allegiance to any approach (or solution). Today, we believe that our approach using the PlasmaCap technology is the best solution to this new problem, but as we invest and become committed to the solution we have developed, we must and do ensure that our scientists continue to challenge their own solution on daily basis in search of improvements, lest we too fall in love with the solution and not the problem.

References

  1. Plasma Protein Therapeutic Market Size, Share & Trends Analysis Report By Product (Albumin, Immunoglobulin, Factor VIII), By Application (Hemophilia, PID, ITP), By Region, And Segment Forecasts, 2018 – 2025. Rep. Grand View Research. Dec. 2018. Web.
  2. MRB: The Worldwide Plasma Proteins Market 2016 (Published Dec 2017).
  3. MRB Data: Worldwide Report 2017 “The Plasma Industry: A Look to the Future.” Marketing Research Bureau. n.d. Web.
  4. Plasma Protein Therapeutics Market to Rise US$31 Billion By 2024.” Market Watch. 30 Jan. 2019. Web.
  5. MRB: IgG 2018-2025 US Forecast Data Report (Published 2019).

Nicholas Green

Nick currently serves as President & CEO of Therapure Biopharma Inc. of which Evolve Biologics is a division, and previously served in senior executive roles for several contract manufacturing organizations and life sciences companies, including Managing Director of Nipa Laboratories Ltd, Head of the Life Sciences Division of Clariant International Ltd, President and CEO of Rhodia Pharma Solutions and President of Codexis Pharma Division. Nick is also a current Board Member at Induce Biologics Inc. Nick holds a BSc (Hons) in chemistry from Queen Mary University of London and an MBA from the University of Huddersfield in the UK.