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European Biopharmaceutical Review

Learning Curve


The emerging field of cell therapeutics has a lot to learn from the monoclonal antibody’s journey to commercial success, particularly when it comes to viable and cost-effective manufacturing strategies.


Over the years, the biotechnology industry has created lifesaving products of increasing complexity. Following the initial emergence of recombinant protein technologies, low dose hormones and growth factor products, therapeutic monoclonal antibody products formed the ‘new’ wave of biotechnology products. The advance of next generation antibody therapies such as antibody-drug conjugates, engineered, enhanced, and bispecific antibodies and fragments quickly followed, offering more in the way of ‘personalised medicine’, with an array of antibody-derived products which can be chosen to meet the specific needs of the clinical indication and the individual patient.

Today, a new and yet more complex therapeutic modality is emerging as cell therapies and ‘regenerative’ medicines are developed for use in diseases that are not amenable to treatment with more classical pharmaceutical or biopharmaceutical products. This field holds the promise of regenerating damaged tissues and organs in the body by replacing the damaged tissue and/or by stimulating the body’s own repair mechanisms to heal previously irreparable tissues. Cell therapies are being developed to address a large number of previously unmet medical needs, including degenerative diseases, acute injuries, cancer and some genetic deficiencies. These therapies hold great promise, but face challenges in becoming commercially viable and cost-effective.

The transition from the initial discovery of monoclonal antibodies to the licensing and distribution of the first successful products took more than a decade, and even the first commercial products had sub-optimal properties. Biopharmaceutical companies and global regulatory agencies have developed a large knowledge base concerning the critical quality attributes of monoclonal antibodies, and the manufacturing and testing requirements for this class of products are clearly elucidated in multiple formal guidance documents. The transition of cell-based therapies from early development to full commercial success is likely to take a similar period of time and require the coordinated efforts of scientists and regulators to develop a complete understanding of the critical quality attributes of cell therapies and the impact of different process conditions on these attributes. However, there are lessons to be learned from the monoclonal antibody's journey to commercial success in terms of the manufacturing challenges and solutions, because the methodical approaches to developing solutions can be applied to cell therapies as these cutting edge medicines proceed through the clinic and onto the market. Here we describe the hurdles that were faced by the early developers of monoclonal antibodies and apply the lessons learned to the emerging field of cell therapy.



A Brief History of Monoclonal Antibodies

In 1984 Kohler and Milstein received the Nobel Prize in Medicine for their pioneering work on the production of monoclonal antibodies (1). The creation of an immortalised cell line as a continuous source of a single antibody revolutionised the use of these products in medicine and enabled the development of highly specific antibodies directed toward a single epitope. The development of monoclonal antibodies as therapies for human disease commenced shortly after their discovery and by 1986 Orthoclone OKT3 (Ortho Pharmaceuticals), the first monoclonal antibody for human use, was approved for prevention of kidney transplant rejection.

The enthusiasm for therapeutic monoclonal antibodies continued through the 1990s with the next wave of antibody products generally being developed as anti-cancer agents. As shown in Figure 1 and Figure 2, several additional monoclonal antibody products eventually gained approval through the decade, and many of these products are among the top 10 biopharmaceuticals on the market today.





Monoclonal antibodies are now the dominant class of biopharmaceutical products on the market, with 2010 sales in the US and Europe of approximately $46 billion – an increase of 12 per cent compared to approximately $41 billion in revenues in 2009 (2). The path to creating manufacturing strategies and products that enabled this commercial success was not easy and may hold lessons for the emerging class of cell therapies. When monoclonal antibodies were initially developed, regulators and scientists alike were concerned about their complexity compared to previously approved biologic products. The challenges of manufacturing antibodies in a safe and reproducible manner were initially seen as hindrances to commercial success, but the industry has met and conquered these challenges.

Hurdles in the Development of a Therapeutic Product

While monoclonal antibodies are now a well-established product class, reaching the current status quo for antibodies was not a smooth path. Issues such as the immunogenicity of the earliest antibody products, low productivity of manufacturing technologies, and challenges in making a consistent product with the inherent variability of cell-based expression systems, all contributed to delays and set backs as these products were developed. It is safe to say now, however, that the industry focused on solving these problems and moving forward to develop monoclonal antibodies into the generally safe and effective therapies that they are today. Cell therapy will face similar hurdles, but with the necessary attention and resources, the industry will solve these problems and advance new therapies into the market to treat currently untreatable diseases.



Immunogenicity

OKT3, the first therapeutic monoclonal antibody on the market, consists of a fully murine antibody sequence and is therefore seen by the human immune system as a foreign protein. Monoclonal antibodies such as OKT3 and other murine antibodies in development faced significant clinical issues caused by the human anti-murine antibody (HAMA) response in patients receiving repeated doses of monoclonal antibodies in clinical trials. The HAMA response neutralised their effectiveness and resulted in their rapid clearance. For example, it has been reported that OKT3 can elicit a HAMA response in up to 86 per cent of patients treated, leading to limitations in its efficacy (3).

To overcome the HAMA responses, techniques enabling the creation of ‘chimeric’ antibodies with murine variable regions and human constant regions were developed that helped to lower the HAMA responses. Further, because the antibody constant region in these chimeric antibodies is human, it is capable of activating other components of the human immune system to potentially create more effective therapeutic agents. Many of the therapeutic monoclonal antibody products approved in the late 1990s and early 2000s are chimeric antibodies, including such products as Rituxan (approved in 1997) and Remicade (approved in 1998). To further reduce the murine component, technologies that generate ‘humanised’ and even fully human antibody products followed. Like chimeric antibodies, humanised and fully human antibodies can activate other parts of the immune system to increase the potential efficacy of the monoclonal antibody product. Among the humanised monoclonal antibody products on the market today are Herceptin (approved in 1998), Xolair (approved in 2003) and Avastin (approved in 2004). In addition, Humira (approved in 2004) was the first fully human antibody to be approved for therapeutic use, and several additional fully human antibodies are now on the market.

Immunogenicity is also one of the major hurdles facing cell therapies, as there is the potential to develop immune rejection towards non-autologous cells. A cell therapy originating from a donor cell line, or an allogeneic product, may have cell surface antigens that are foreign to the patient to whom the product is administered. Transplantation or administration into areas that are less protected by immune surveillance, such as the brain, is a potential option for some cell therapies, but is obviously dependent on the disease indication that the product is intended to treat. Other strategies, such as banking of MHC-compatible cell lines to match to the intended recipients, may also be feasible, akin to the approach taken when matching organs for transplant. The industry should focus on understanding and controlling the manufacturing and administration of cell therapy products to reduce immunogenicity. The development of suitable immunosuppression protocols will enable these medicines to provide much needed clinical benefits.

Process Optimisation

Complex products must be manufactured cost-effectively to meet the market demands and to achieve commercial success. Enabling sufficient productivity to meet commercial demand was a major challenge for early monoclonal antibody products. The relatively high doses required for most antibodies forced the biopharmaceutical industry to focus on improving the productivity and efficiency of manufacturing processes, particularly focusing on increasing the protein production level (titer) that was achievable in the cell culture bioreactor and the overall purification yield in downstream processing. Early on, expression levels in cell culture for monoclonal antibodies were typically on the order of 100-500mg/L. Even as recently as five years ago, antibody titers in excess of 1g/L were not common, and many products were launched using production cell lines and manufacturing processes with bioreactor titers of 0.5-1.0g/L (4). The industry and societal pressure to produce more product at reasonable costs pushed process scientists and engineers to develop methods for generating high expressing production cell lines and culturing these cell lines for maximum productivity. The optimisation of cell lines and fed-batch processes over the past 20 years has led to steadily improving antibody titers so that today titers of 5g/L or more are becoming routine, and the cost of goods for future products is therefore decreasing (5).

A significant contribution to the improvement of antibody manufacturing processes was the establishment of the Chinese hamster ovary (CHO) cell as the platform production host cell line for antibody production. The widespread adoption of this host cell has led to a better understanding of the growth characteristics, metabolism, behaviour in bioreactors, virulence factors, and the likely host cell-related impurities that might be in a process or product. Further, because there is a strong regulatory history with CHO cells, more and more products in development are made using CHO cells. Therefore, establishment of a platform cell line and process across the industry has reduced technical and regulatory risk for new product development and has reduced the commercial cost of goods for products that use the new production technologies.

Unique Cell Therapy Challenges

From a manufacturing viewpoint, a cell therapy is a complex challenge. Cells are living, dividing entities that cannot be simply described by a chemical formula or even by the many commonly accepted analytical methods that are used to confirm the identity, purity, potency, safety and quality of an antibody product. Cell preparations are not homogenous and can constitute a complex mixture of cell types, including cells with varying differentiation capacity and multiple differentiation stages, for example. The cell's capacity to differentiate in vivo and mode of action may strongly depend on the conditions and time of in vitro culture, such as the use of growth factors and separation methods employed. It is therefore essential that preclinical and clinical studies are performed using well-defined and characterised cell preparations, derived using a robust manufacturing process to ensure consistent and reproducible quality of the final product. To mitigate risk in the manufacture of cell therapies, companies developing these therapies need to rely on control of the manufacturing process itself, including the choice and preparation of starting material, in process control and release testing.

The attention paid to cell therapy product characteristics and performance during production is highly warranted. When transplanted into a living human, cells respond to chemical and hormonal signals and may even migrate to a different part of the body than the intended therapeutic locale. Monitoring and quantifying cell properties that would affect performance is currently very difficult and must be addressed by the conductance of clinical trials to demonstrate the safety and efficacy of any such treatment. In general, the same safety requirements for traditional biopharmaceutical products such as antibodies also apply to cell therapies, however there are also some unique risk factors for cell-derived products. An important safety concern is the capability of, in particular, embryonic stem cells and induced pluripotent stem cells, to form teratomas. Although benign, their formation in anatomically sensitive positions, such as the CNS, is an important safety concern, and the risk of ectopic engraftment in non-target tissues must be addressed. It is also acknowledged that additional appropriate structural and morphological endpoints may be necessary in order to study regeneration, repair or replacement of a tissue (6).

The ‘scale-up’ or ‘scale-out’ of cell therapies to meet the demands of late stage clinical trials or commercialisation brings its own challenges, and therefore must be considered during early process development to avoid costly changes late in the manufacturing process that could impact on product launch.

With autologous therapy, small batch sizes intended for a single patient can be manufactured, but the documentation and testing requirements for such production are considerable when costed on a per-patient basis. Autologous technologies have a tendency to follow a ‘service’ business model and bring with it the challenges of multiple manufacturing sites and processing centres. Dendreon’s Provenge was approved by the FDA in 2010 and they are now progressing down the route of increasing manufacturing capacity for the ‘scale-out’ of production.

Conversely, allogeneic treatments are often manufactured centrally and are generally capable of ‘scale-up’ to accommodate larger batch sizes. One of the principle challenges of an allogeneic therapy is maintaining product and process consistency through the different stages of development, including production at different manufacturing sites, at different scales and taking into account changes in raw materials and production methods.

In addition to the economies of scale and the technology improvements, the introduction of automated procedures is also commonly being evaluated by cell therapy companies to help lower costs. This is similar to the drive to increase production titers for antibody products in order to make them more cost-effective to manufacture. Cell therapy companies can look towards the steps that antibody companies took to optimise processes and reduce manufacturing costs for guidance on methodical approaches to process optimisation, albeit with the added challenges that cell therapies pose in terms of product quality considerations.

One often overlooked and unanticipated cost driver is the lengthy patient follow-up required with a regenerative medicine product. Geron report that in their Phase 1 GRNOPC1 Spinal Cord Injury Trial, the trial protocol includes multiple MRI scans during their follow up. After one year of initial monitoring, patients enter a period of long-term follow-up that includes annual in-person visits for the first five years and subsequent yearly check-ups via telephone for an additional nine years (7).

Continual Improvement in Antibody and Cell Therapy Manufacturing

The advances in cell line generation and cell culture for antibodies described above have enabled companies to produce monoclonal antibodies at very high expression levels and very reasonable costs. As a result, early concerns that the industry would not be able to meet the growing demands for production of monoclonal antibodies have subsided. While these significant improvements in upstream production have resulted in the ability to routinely express monoclonal antibodies at high titers, the capacity and ability of downstream processes to handle these high quantities of antibody is the new bottleneck and the new focus area for process scientists. In addition, companies today are striving to incorporate quality by design and other new regulatory concepts into the development of monoclonal antibody products to further reduce the cost and development timelines for these products without adversely affecting their quality.

Cell therapy and the related regenerative medicine products that are now in development are at the cutting edge of a new therapeutic paradigm, whose applications across a broad spectrum of disease can be anticipated if these therapies prove to be as effective as the initial reports suggest. The industry should focus on developing production technology and support that will enable cell therapies to be produced, tested, transported and administered cost-effectively and safely. Today’s quality initiatives that are directed toward detailed process and product understanding, knowledge of raw materials and process interactions, and definition of operational design space should be considered and implemented in cell therapy development programmes to improve the manufacturing processes and product consistency and quality. The lessons from the early days of monoclonal antibody development can help guide the efforts in this new therapeutic modality.

References

  1. Kohler G and Milstein C, Continuous cultures of fused cells secreting antibody of predefined specificity, Nature 256 (5,517): pp495-497, 1975
  2. BioProcess Technology Consultants, The state of mammalian cell culture capacity 2011, Woburn (MA): November, p149
  3. Mather JP, Worsley S, Fisher J, and Vehar G, A view of antibody therapeutics Part 1: from failure to market leader, BioExecutive International 42: 2005
  4. Adamson SR, The role of technology and science in manufacturing economics, presented at: IBC Antibody Development and Production Conference 2007, 28 February- 2 March; San Diego, CA
  5. Butler M, Animal cell cultures: Recent achievements and perspectives in the production of biopharmaceuticals, Applied Microbiological Biotechnology 68 (3): pp283-91, 2005
  6. European Medicines Agency, Reflection paper on stem cell-based medicinal products EMA/CAT/571134/2009
  7. Visit www.geron.com


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Susan Dana Jones is Vice President and Senior Consultant with BioProcess Technology Consultants, and is a seasoned biotechnology entrepreneur with experience in product development, outsourcing and strategic planning. Susan is an expert in cell line development and characterisation and is a leader in applying the principles of quality by design to early stage biopharmaceutical development programmes. She has co-founded two successful biotechnology companies and has managed multiple discovery and product development programmes. Susan was formerly VP Manufacturing at Waratah Pharma and has held positions at Dyax, Avant (now Celdex) and the Dana Farber Cancer Institute. She currently serves on the Board of Directors of Gene Solutions, the Scientific Advisory Board of Symphogen, and is a member of the Editorial Advisory board of BioProcess International. She received her PhD in Genetics from the University of California, San Francisco. Email: sjones@bptc.com

Howard L Levine is President and Principal Consultant of BioProcess Technology Consultants and Managing Director of BPTC Europe, and has over 30 years of experience in the biopharmaceutical industry. Prior to founding BPTC to provide technical and business assistance to biopharmaceutical clients, Howard was Vice President of Manufacturing Operations at Repligen Corporation. Before Repligen, Howard held positions of increasing responsibility in process development and manufacturing at Genentech, Amgen and Xoma. Howard holds a PhD in Chemistry from the University of Chicago and completed a post-doctoral fellowship at Harvard University. Email: hlevine@bptc.com

Susan McKee has over 16 years of experience in the biotechnology industry, and joined Angel Biotechnology as Business Development Manager in 2010. She is responsible for realising new opportunities for cGMP contract manufacturing services in the cell therapy and the wider biologics industry, including recombinant protein and bacteriophage production. A graduate of Stirling University with a BSc in Biochemistry, Susan began her career at PPL Therapeutics, before moving into commercially focused roles, including that of Business Development Manager at Genecom Ltd and the Protein Fractionation Centre. Email: susan.mckee@angelbio.com
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