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Cynthia A. Challener, PhD, is a contributing editor to BioPharm International.
Plasma-based proteins and cell-based therapies have significant potential to address unmet medical needs.
Blood is essential to life and also serves as a source of materials with significant therapeutic value. Of the four main components of blood—plasma, red blood cells, white blood cells, and platelets—plasma and white blood, or immune, cells have been used to develop treatments for a wide range of diseases. Various serious, rare, and sometimes life-threatening conditions have been treated for decades with proteins isolated from plasma donated by healthy people. Although autologous cell therapies have only existed for 20 years or so, development of cell-based treatments has accelerated in recent years, with thousands of candidates advancing through the clinic. Each of these types of blood-derived therapies faces its own range of challenges, but demand for both classes of drugs is expected to remain strong for the foreseeable future.
Within human blood, plasma comprises the largest component at approximately 55%, with the remainder red blood cells (44%) and white blood cells and platelets (1%). Plasma is the clear, yellowish, liquid portion of blood and comprises water (>90%), proteins, and other cellular components. It is collected from healthy adults via a process known as plasmapheresis. In the body, the role of plasma is to transport cell, nutrients, and other materials, thus enabling many important physiological functions such as blood clotting and immune responses.
Via a manufacturing process that can take 7–12 months, different proteins are fractionated from the donated plasma and converted to different protein-based therapeutics, according to Mathew Gulick, director, global communications, the Plasma Protein Therapeutics Association (PPTA). Because they are isolated from donated plasma and there are no generic alternatives, protein plasma therapies fall into the regulatory class of sole-source biologic products.
These therapies are used to treat people with conditions such as primary immune deficiencies (PIDs), bleeding disorders, hereditary angioedema, Alpha-1 antitrypsin deficiency, and certain neurological conditions. Generally, plasma-derived therapies replace missing or deficient proteins and are, therefore, administered via injection or infusion on a repeat basis.
There are thousands of different proteins that can be fractionated. The most common include immunoglobulin (Ig or IgG), which is an antibody, and albumin, which is a protein. Others include clotting factors such as fibrinogen, prothrombin, and proteins such as C1 esterase inhibitor and alpha-1-proteinase inhibitor.
Convalescent plasma (CP) is plasma obtained from patients who have recovered from an infectious illness and thus generated antibodies to the disease. It can be used as an emergency measure when other treatments are not available. Unlike recombinant monoclonal antibodies engineered to bind to a specific target, CP possesses a range of antibodies to a viral antigen that provide better coverage by interacting with different parts of that antigen, according to Vu L. Truong, founder, CEO, and director at Aridis Pharmaceuticals.
There can be some challenges with using CP, however, Truong notes. One person’s plasma may not be compatible with another’s. In addition, the level of antibodies in donated plasma can differ from donor to donor. For COVID-19 patients, there is also a shortage of supply. “The limitations for ongoing use of CP may include lack of consistency in specific antibodies in each dose, blood type-matching requirements, and complexity of regulatory oversight because it is not a standardized product with a regulatory approval,” adds Laura Saward, senior vice-president of the therapeutics business unit at Emergent BioSolutions.
In the United States, FDA issued the first Emergency Use Authorization in late August 2020 for investigational convalescent plasma for the treatment of COVID-19 in hospitalized patients (1). Although the data demonstrating strong efficacy have been variable among different studies, CP treatment has been shown to be relatively safe and well tolerated and has a useful role in treating patients infected with the SARS-CoV-2 virus that are severely ill and not responding to antiviral or other antibody treatments, according to Truong.
Given limitations surrounding CP, there is a desire to transition to more consistent plasma-based treatments for COVID-19. IgGs—which have a long history as a safe and effective treatment of many indications including as potential therapeutics against a wide range of pathogens (viral, bacterial, toxins)—can be used to generate hyperimmune globulin (H-Ig) products, according to Saward. “H-Igs are polyclonal IgGs that have been enriched for antibodies with specific titer to a target pathogen, leveraging the immune response in humans or animals and offering the benefit of containing a broad range of antibodies to inhibit a pathogen through different mechanisms,” she says.
The CoVIg-19 Plasma Alliance, a partnership of the leading plasma companies spanning plasma collection, development, production, and distribution, is developing an investigational H-Ig prepared from the pooled plasma of donors with high titers of antibodies against COVID-19. “H-Ig products have been found to be effective in the treatment of severe acute respiratory infections of viral etiology and may present the potential to treat high risk COVID-19 patients,” says Julie Kim, president of the plasma-derived therapies business unit for Takeda Pharmaceutical Company, a founding member of the Alliance.
In just months, the Alliance established the processes to collect convalescent plasma, manufacture the H-Ig, and support the initiation of a rigorous multi-national pivotal clinical study in October 2020 to evaluate four different H-Ig candidates. CoVIg-19 is currently under evaluation as part of a global clinical trial (INSIGHT013) coordinated by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). The results of this study will form the foundation for potential regulatory submissions for the H-Ig, according to Kim.
Meanwhile, Emergent has leveraged its experience with H-Ig development and its validated platform to expedite development of a product to address COVID-19, initiating a comprehensive clinical program and key partnerships, according to Saward. Its candidate, COVID-HIG, is supported by funding from the Biomedical Advanced Research Development Authority and the US Department of Defense (DOD) and is currently being evaluated in a global Phase III NIH/NIAID study as a treatment for hospitalized patients with COVID-19. Another study is being planned for patients with mild-to-moderate COVID-19 at high risk of progression to severe disease. COVID-HIG is also being developed for potential post-exposure prophylaxis, with a clinical program initiated at the end of 2020.
“Even as vaccines are authorized for use and are more widely available, COVID-HIG has the potential to continue to further address segments of the population that are recalcitrant to vaccination, immunocompromised, or excluded from vaccination (e.g., infants, pregnant, other exclusions) until approved and require different forms of prophylaxis or treatments,” Saward observes.
Cell therapy is the transfer of intact, live cells into a patient to help lessen or cure a disease, according to the American Society of Gene and Cell Therapy (2). The most common type is blood transfusion. Bone marrow transplants are another well-established example.
Cells can be of a fixed type (primary) or have the ability to transform into other types of cells (pluripotent such as embryonic stem cells, induced pluripotent stem cells, and multipotent such as hematopoietic and mesenchymal stem cells). Differentiated adult immune cells are also widely used to develop immunotherapies.
Cells collected from patients can be used to produce autologous (patient-specific), while cells donated by healthy people are used to produce allogeneic (off-the-shelf) cell therapies. Either type of therapy can involve isolation of the desired cell type followed directly by expansion, or genetic manipulation of the cells to boost their ability to killed diseased cells (i.e., chimeric antigen receptor [CAR]-T cells) prior to expansion.
There is a strong clinical need for both plasma-derived and cell therapies. “Takeda has seen a worldwide increase in demand for plasma-derived therapies, reflecting how essential they are for treating patients with rare, life-threatening, chronic and genetic diseases,” observes Kim. “We believe this increase, especially for Ig, is being driven by better diagnosis rates and increased patient screening in developed markets, as well as improvement in the standards of care in emerging markets,” she says. This trend is also reflected at an industry level.
Technological advances also now allow for individuals relying on these therapies to be diagnosed earlier in life, and as children grow into adulthood, their dosage volumes increase, adds Gulick. He also notes that innovation has resulted in treatment improvements, such as subcutaneous products that grant patients greater freedom to administer treatment at home but often require higher doses.
In addition, expanded treatments of secondary immune deficiencies are also now helping others with compromised immune systems, such as cancer patients, but also requires greater amounts of plasma-derived therapies, according to Gulick. There is also growing demand for Ig because it is increasingly being used in a number of new indications beyond primary and secondary immunodeficiency disease, including neurological conditions, such as chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy, he adds.
“Finally,” Kim observes, “as science progresses, we are discovering the potential utility of previously untapped proteins in plasma that may help with a range of diseases with few or no treatment options.” One example is plasma-derived inter-alpha inhibitor protein (IAIP). Takeda has signed a global licensing agreement with ProThera Biologics to evaluate the therapeutic potential of IAIP, a protein found in plasma that functions as an immune modulator to inhibit acute inflammatory reactions. “With this broad mechanism, IAIP has a range of potential therapeutic applications, and in preclinical models has shown strong potential in patient populations challenged with high mortality rates, including those with diseases strongly associated with inflammation,” she explains.
While both plasma-derived protein and cell therapies will experience increasing demand, Truong predicts that growth for cell therapies will be greater. In addition, he expects that as the technology for screening B cells advances, engineered antibody therapies, which are much more well characterized than convalescent plasma therapies, will attract rapid interest, potentially replace some existing CP products and experience growth at a faster rate.
“Once it is relatively easy to screen for B cells that produce the most potent monoclonal antibodies (mAbs), the technology for cloning the relevant genes into production cell lines and producing large quantities of those mAbs is relatively straightforward today. This approach avoids the need for plasma donors and allows for the easy scale up of the manufacture of purer antibodies with better-defined targets,”Truong says.
In markets outside of the US and Europe, however, Truong does note that plasma therapies are expanding at a faster rate because the technology involved is not as sophisticated as that required for screening B cells and identifying desired antibodies.
The technologies used to support plasma collection and processing have improved dramatically over time, but there is still room for improvement. Of course, one of the key limitations to sustainable growth for plasma-derived therapies is the need to collect sufficient quantities of plasma. “The quantities of plasma-derived therapies we can provide is fully dependent on how much plasma we can collect,” Kim asserts.
Currently, more than two-thirds of the world’s plasma is collected in the US; that limits the industry’s ability to support the growing population of patients who can benefit from these valued therapies.
To create innovative partnerships and address this urgent need, Emergent formed a number of partnerships across government agencies, blood banks, plasma suppliers, academic centers, and hospital systems, according to Saward. For instance, with support from DOD, the company partnered with Mount Sinai Hospital System and ImmunoTek Bio Centers to establish a new capability for plasma collection onsite at Mount Sinai to be closer to patients that have recovered from COVID-19. “This capability was established quickly during the pandemic, with each party providing complementary expertise to create a new channel for plasma collection within the healthcare system in New York. This partnership provides a model that could be implemented across various sites to enable broader access to plasma closer to potential donors,” she comments.
As an industry, Gulick stresses that efforts are being pursued in conjunction with health authorities and public health organizations around the world to elevate the dialogue around the importance of plasma, with the goal of modernizing outdated regulations that restrict plasma collection and expanding collection infrastructure and processes in more countries. “We are hopeful that the positive awareness of plasma as a potential contributing solution to the COVID-19 pandemic will help foster recognition and support for the broader patient need for plasma around the world, including the need to permanently revise outdated regulations in order to improve availability of plasma,” Kim adds.
Unfortunately, plasma donations declined significantly in 2020 due to the COVID-19 pandemic, and PPTA and its members are urging all healthy adults to donate plasma, according to Gulick. Plasma donation centers have been designated as critical infrastructure and each company is working diligently to return to growth in order to meet patient needs.
As an example, Kim shares that although Takeda has faced some challenges in plasma collection due to the COVID-19 pandemic, which have fluctuated in line with restrictions on movement of people and travel, the company is still on track to achieve its target of >65% growth by 2024 due to the significant investments made in its business and the range of measures taken specifically to mitigate the impact of COVID-19.
One other area of opportunity for increasing the availability of plasma-derived therapies is the development of more efficient isolation technology. Evolve Biologics was created as the plasma products and technology division of Therapure Biopharma specifically to commercialize an alternative plasma protein production technique that eliminates the need for cold ethanol fractionation, the traditional method used for collecting plasma (3). This process, which uses acid, alcohol, and salts at low temperature to precipitate proteins into fractions that must then be resolubilized and further separated, takes months and consumes significant energy. Because it was initially developed to extract albumin, it is also not optimized for most proteins.
Evolve’s PlasmaCap EBA technology uses proprietary affinity adsorbents (dense tungsten carbide beads coated with agarose modified with ligands designed to bind to a specific protein) and expanded bed adsorption (EBA) chromatography to capture plasma proteins directly from plasma without the use of precipitating solvents (3). Proteins are captured in their native form with a higher degree of efficiency and selectivity and in higher yield per liter of donor plasma. Avoiding precipitation also results in the isolation of proteins with more consistent quality and purity.
In addition, the EBA chromatography technology can be readily scaled up or down in response to market demand and allows for small, modular facilities to be built that can leverage locally collected plasma for the supply of indigenous proteins (3). It also has the potential to facilitate the isolation in sufficient quantities of plasma proteins that are not economically feasible to obtain with cold ethanol fractionation because they are present at very low levels, thus enabling the development of new plasma-derived therapies.
Evolve anticipates filing for FDA approval of PlasmaCapTMIG, a 10% liquid formulation intravenous immune globulin (IVIG) product manufactured from US-sourced plasma, as a replacement therapy in PIDs in 2021 (3). Regulatory submission is also expected in 2021 for albumin produced using the PlasmaCap EBA technology.
For cell-based therapies, Truong believes one of the key challenges for those treatments that involve genetic modification is developing more highly controlled methods for imparting molecular changes to cells. For instance, viral vectors are commonly used for gene transfer, but they can create safety issues. “Controlled manipulation of the genome is crucial,” he states. “There are many questions that need to be answered, such as where the gene is inserted into the cellular genome, whether the genetic modification is permanent or transient, and whether the changes will disrupt cellular function in some way or activate other genes with negative effects.” He adds that it is also a challenge to ensure that no changes are introduced during the expansion of cells whether or not they have been genetically modified. “The industry is making a lot of progress in these areas, but they do still present significant challenges,” Truong observes.
Given that plasma-derived protein and cell-based therapeutics are medicinal products, they are highly regulated as is the case for all pharmaceuticals. PPTA member companies adhere to all national and international regulations, including voluntary standards that go beyond regulatory requirements, according to Gulick. “Licensing processes include the review by a regulatory authority of the manufacturing processes, facilities, and equipment plus the safety and efficacy of the therapeutic product as evidenced by studies of the product in targeted populations. Facilities manufacturing the licensed biologics are subject to current good manufacturing practice (CGMP) requirements and are inspected regularly,” he explains.
Furthermore, the “raw” material plasma is regulated far more comprehensively than simple supplier qualification standards, according to Gulick. In the US, the source plasma is an independently licensed product. In the European Union, plasma for manufacturing is extensively scrutinized in a Plasma Master File. Kim adds that there are also policies designed to protect the safety of plasma donors.
The wide variation in regulations around plasma collection and processing between countries still needs to be addressed, Kim says. In some cases, she notes, that regulations actually limit processes and infrastructure for plasma collection. “Given the need for plasma around the world, these regulations can pose a challenge to sustainable supply of plasma therapies. We are actively engaging with peers, professional associations, patient associations, regulators, and governments to increase recognition of the critical importance of plasma sourcing and to encourage sustainable collection of plasma,” she observes.
Several different regulations apply to cell-based therapies. For some autologous products, good tissue practices are applicable, according to Truong. All manufacturing processes must comply with CGMP requirements. Demonstration of genetic stability is necessary for genetically modified cells. Allogenic products must be shown to be non-allergenic. Many cell therapies are frozen for distribution, and thus it is essential to show that when recovered from the frozen state there is no damage to the cells that will impact safety or efficacy.
“It is important to remember, though,” Truong remarks, “that many cell therapies are used to treat patients that have no other treatment options available to them. Regulators have an incentive to work with the pharma industry and cell therapy developers to bring these novel solutions to the market as safe and effective therapies for patients in dire need of medical assistance.”
Both plasma-derived proteins and cell-based therapies have potential to address many unmet medical needs. “Blood- and plasma-derived therapies will continue to provide solutions for a range of indications that cannot readily be addressed otherwise, with a number of organizations exploring the potential for recombinant polyclonal antibodies; these products are still in development,” Saward asserts.
For future therapies, she notes that there remain a number of opportunities to leverage the complex natural immune response in order to develop therapeutics against many challenging diseases. “As the COVID-19 pandemic has underscored, blood- and plasma-derived therapies are amongst the first to be deployed against emerging infectious diseases considered public health threats. These applications also transcend into potential applications to address drug resistance in bacterial and fungal infections,” Saward says.
With demand for plasma-derived therapies continuing to outpace supply, Takeda sees an important opportunity and responsibility to build on its more than 75-year legacy in plasma and rethink every aspect of its business to ensure the company meet the needs of patients worldwide, according to Kim. “We believe there is an incredible untapped opportunity to innovate for the benefit of patients. Only a fraction of the 3000+ proteins that circulate in plasma has been tapped for therapeutic applications,” she says.
Takeda’s strategy is to work on both complete care solutions that integrate complementary technologies and devices to improve the experience for those who rely on current plasma-derived therapies and seek to discover new ways in which proteins in plasma might address a significant number of diseases with few or sub-optimal treatment options today. The company is not only making long-term investments to increase the capacity, but also investing in automation, AI, and analytics capabilities.
Underlying these efforts is recognition that plasma-derived therapies can only be made from human plasma donated by healthy individuals. “If we are to realize the full potential of plasma, we must create the conditions that can deliver increased and sustainable plasma availability long term,” Kim insists. “That is why we are working closely with policy makers, regulators, patient organizations, and industry partners to advocate for change. This includes bringing a deeper appreciation that domestic plasma collection can secure better, more sustainable access to plasma-derived therapies and showing where regulations and policies, such as donor acceptance criteria, donor deferral times, and inventory hold periods, require updating urgently in line with current scientific information,” she says.
While plasma-based therapeutics have been around for decades, the potential of cell therapy is just beginning to be realized. “There are many complex diseases that cannot be treated with antibodies, proteins, or enzymes, but for which engineered cells offer the potential to ameliorate or even cure,” Truong observes. “While most of the current effort is focused on autologous solutions, allogeneic cell therapies may have the greatest potential due to the reduced logistics issues and ability to scale up manufacturing (rather than scale out). Both approaches, however, present tremendous growth opportunities,” he concludes.
1. FDA, “FDA Issues Emergency Use Authorization for Convalescent Plasma as Potential Promising COVID–19 Treatment,” Press Release, Aug. 23, 2020.
2. ASCGT, Gene and Cell Therapy FAQ’s, www.asgct.org, accessed Dec. 21, 2020.
3. D. Holliday and M. Krause, “Therapeutic Potential of Novel Plasma Protein Production Technology,” Pharma’s Almanac, Sept. 29, 2020.
Cynthia A. Challener, PhD, is a contributing editor to BioPharm International.
Vol. 34, No. 2
When referring to this article, please cite is as C. Challener, “Exploring the Therapeutic Value of Blood Components,” BioPharm International 34 (2) 2021.