Fibroblast Growth Factor’s remarkable biological function, now newly formulated for cell therapy use
The fibroblast growth factor (FGF) family counts 22 characterized members – since their discovery over 6 decades ago, the FGF proteins have been linked to essential roles which include cell proliferation, differentiation and apoptosis, embryonic development and differentiation, neuron differentiation, survival and regeneration, normal skeleton development, and the proliferation of various types of cells.
Other roles include the regulation of vitamin D metabolism and osteogenesis and post-natal bone mineralization by osteoblasts, with new evidence supporting their regulation of appetite control.
Just recently, more significant implications about FGF in tissue regeneration were reported. The lab of Dr. Atsushi Kawakami at the Tokyo Institute of Technology published, in the journal Development, their observations on the mechanism by which FGF signaling is involved in tissue regeneration. They studied this by investigating the regeneration of damaged fins in zebrafish, and identified FGF-20a and FGF-3/10a as major FGF ligands in wound epidermis and blastemas, respectively, important for the regeneration process. Because FGF-20 and FGF-3 are present in all vertebrate species, this study may uncover potential cues to how tissue regeneration is regulated in mammals, as well as humans.
Clinically, studies such as the above one, as well as discoveries made over the past few decades have resulted in an increasing focus from the part of pharmaceutical and cell therapy companies developing biologics to target FGF receptors that are implicated in important therapeutic functions via their signaling and regenerative roles. Companies such as Boehringer Ingelheim are involved in clinical studies for new biologics targeting, among others, signal transduction pathways regulated by FGF.
And the market has responded – FGF is ubiquitous and readily available. It can be found stable, functional, and lyophilized, often with excipients to improve its stability.
However, as the clinical development of biologics advances – and such advances are progressing rather rapidly – so should the industry’s response to the shifting needs of clinical developers. Such needs include a more thorough consideration on safety, sterility and cell therapy use.
While Akron has been a strong, leading supplier of multiple FGF proteins for many years, we have now gone one step further and developed a formulation of FGF which directly addresses the use of the protein in cell therapy settings.
Our new FGF is a ready-to-use, fully-formulated and reconstituted, liquid-phase FGF basic. Having formulated FGF in liquid form makes the protein amenable to single use scenarios and eliminates the need for cumbersome reconstitution. In doing so, we have addressed common contamination issues that arise during handling of the powder. Moreover, sterility, critical in cell therapy processes, is maintained in a single-use configuration.
Filled to multiple sizes, the new liquid FGF is a revolutionary solution that removes ambiguity during use, being formulated to exact activity specifications.
As a first step to showing you how this new FGF can simplify and improve your workflow, contact us to discuss – we would be happy to learn about your application.
Fibronectin’s new implications in wound healing + Akron to present course at Amgen’s Bioprocessing Center
Following on from last week’s post on our capabilities to exclusively derive virus-inactivated fibronectin as the first such type of fibronectin on the market, this week we want to expand and highlight two new studies that have implicated fibronectin as having key roles in wound repair.
As widely known, fibronectin is one of the key proteins of the extracellular matrix, and has significant implications in wound healing and repair as well as cell growth. In brief, during the wound healing process, fibroblasts grow and produce fibronectin as well as other protein such as collagen that form a new extracellular matrix to fill the wound bed. This process has been studies extensively, as has fibronectin’s key role in cellular adhesion and growth. Two new studies highlight how fibronectin can be implicated, positively or negatively, in both wound healing as well as cell growth processes.
The first study, by Dr. Jonathan Garlick’s lab at Tuft’s University, is titled
Altered ECM deposition by diabetic foot ulcer-derived fibroblasts implicates fibronectin in chronic wound repair and is published in Cellular Reprogramming.
The authors investigated the wound healing process of diabetic foot ulcers (DFUs). DFU-derived fibroblasts were compared to healthy ones in their ability to generate the ECM during the wound repair process. the authors discovered that fibronectin generated by DFUs was deficient in its ability to promote growth factor beta regeneration, indicating it as they key protein regulating the process.
The second study looks at the role of fibronectin from a biomaterials perspective. Titled ”
Fibronectin-modified surfaces for evaluating the influence of cell adhesion on sensitivity of leukemic cells to siRNA nanoparticles,” it was published by the lab of Dr. Hasan Uludağ at the University of Alberta in Canada in the journal Nanomedicine. The authors have demonstrated that fibronectin (FN)-grafted (by crosslinking), plasma-treated PTFE surfaces can be used as suitable platforms to investigate the influence of leukemic cell adhesion on siRNA treatment. Improved adhesion and growth of chronic myeloid leukemia K562 cells was possible on FN-grafted surfaces.
Akron at Amgen Bioprocessing Center
We are pleased to announce that Akron Biotech will participate in an industrial/academic training course at the Amgen Bioprocessing Center at the Keck Graduate Institute in Clermont, CA. Akron will lecture participating delegates, who will attend an intensive hands-on course on Bioprocessing, on proteins and their use in bioprocessing – from structure and function to purification techniques and analytical measurements. The course starts on September 19th.
The extracellular matrix protein fibronectin is involved in a remarkably important set of functions that go beyond cell migration and adhesion, and encompasses disease control, as well as the structural integrity and functional properties of live tissues, and was recently shown to be important for its therapeutic effects in nanomedicine.
Fibronectin can be sourced from plasma or it can be cell-derived. As therapeutic systems which use fibronectin as an ECM component progress through the development pipeline, considerations about the sourcing and safety of those products for which fibronectin is part of the final formulation are becoming increasingly more important.
While removal and inactivation of adventitious and endogenous viruses is critical to the safety of the final product and is required by regulatory agencies, few changes have occurred to the manufacturing processes of plasma fibronectin to eliminate potential viral contamination from the source plasma over the years. By and large, plasma fibronectin is produced using animal-derived processes that have been in place for the past three decades.
Regulatory guidances provide a general framework for how demonstration of viral clearance should be performed, but they do not provide any comment about how to achieve such viral elimination. As far as fibronectin is concerned, no products have emerged on the market which address the inactivation of potential viruses from source plasma.
In order to combat this, we have introduced the first virus-inactivated fibronectin to the market recently. The product is fully validated and sourced from plasma which has been treated so as to inactivate any potential adventitious viruses.
The virus-inactivated fibronectin is available as a GMP product with a portfolio of documentation which includes batch records and well as prolonged stability data.
Functionally, virus-inactivated fibronectin is equivalent to the traditional non-virus-inactivated variant, with structural and functional homology – in other words, it is the same product. This is advantageous as it minimizes the characterization work that one would have to perform in order to introduce it into their process or switch from the regular fibronectin.
As the first of this kind on the market, the product has been verified in a number of studies and we are happy to discuss data with you.
Even a cursory glance at general media over recent weeks would have indicated an increased amount of coverage dedicated to immunotherapy. Partly linked to recent developments in the filed, most major outlets have, in the past few months, chimed in, in one way or another, in a response to the major headlines.
As an example, this week, the New York Times asked “What Is Immunotherapy?” in an article that followed on from recent NY Times reports commenting on the recent stem cell clinic data and the temporary halt of Juno Therapeutics’ CAR-T trials.
Others have followed suit, reflecting what the media appears to perceive as a momentum that the field is currently enjoying. Yet there is optimistic caution, with the field and its treatments being called “controversial” in some reports. Such claims are understandable, especially due to the reactory nature with which the media operates.
But positives have emerged from these media reports as well.
These recent developments have renewed discussions about topics as varied as the operation of stem cell clinics as well as, more generally, the safety and efficacy of cell and gene therapy-based treatments.
Spurred by recent developments, questions about regulations and the role of the FDA in overseeing and approving these immunotherapies have been raised – these questions aim at tackling issues with respect to the regulatory landscape that accompanies cell and gene-based immunotherapies.
On one hand, the FDA has been praised for the speed with which it has kept up with these fast-developing discoveries in the CAR-T and 3D printing arena as they pertain to clinical therapy, while on the other, the Agency has been called to provide tighter oversight and more regulation to the field.
These discussions have renewed interest in new initiatives that have emerged aimed at easing the path to market for these new therapies.
Some are looking to Japan for inspiration: new regulations accelerating the approval of regenerative therapeutics in Japan took effect Nov. 25, 2014. These are The Act on the Safety of Regenerative Medicine and The Pharmaceuticals, Medical Devices Act. The main benefit of these new regulations is that they enable companies to receive conditional marketing approval and generate revenue from regenerative products while trials are being conducted.
And just like Japan, a controversial proposal, which we wrote about recently, by the Bipartisan Policy Center—to open up a conditional approval pathway for the FDA to conditionally approve—at its discretion— conditionally approve certain cell therapies that have a lower risk profile—for a limited period of time prior to the full clinical trials are complete.
Whether this the right path forward is for a separate discussion, but a greater awareness of the therapeutic frontiers of cell therapy will ultimately fuel a greater involvement—from both the public and regulatory sectors—to push these frontiers forward, which can only be a good thing.
Translating academic research to clinical products: The case for improved interaction between academia and industry
Most commercial cell therapies originate form research funded at academic institutions. Yet despite the large amount of funding invested in academic research, the number of therapies that reach commercial stage is low, and the pace at which such translation occurs has been lagging.
Over the last few years, the Tissue Engineering & Regenerative Medicine International Society-Europe (TERMIS-EU) Industry Committee as well as its TERMIS-Americas (AM) counterpart has been involved in supporting programs aimed at addressing challenges associated with translating academic research into commercial cell therapy products. The TERMIS-EU Industry Committee has also strongly encouraged a tighter interaction between academics and industry via collaborative projects.
A number of findings from these efforts were outlined in 2014, in an opinion paper titled “Translating cell-based regenerative medicines from research to successful products: challenges and solutions,” and published in Tissue Engineering Part B Reviews. Authored alongside three Termis-EU Committee members, the manuscript outlined the consortium’s position on the challenges faced in speeding up the time it takes for academic research to be translated into practice.
On the heels of such efforts, a collaboration between the Leiden University Medical Center, the Medicines Evaluation Board (MEB) in Utrecht, Royal Free Hospital, University College London and the Technical University Munich’s Cells Interdisciplinary Center for Cellular Therapies, resulted in a manuscript addressing the current state of the industry-academic translation of cell therapies.
The manuscript is titled “Development of cell therapy medicinal products by academic institutes” and was published this Spring in Drug Discovery Today.
Issues such as lack of industrial feedback to academic institutions when developing research projects are discussed – which may be contributing to low clinical progression of academic discoveries, indicating that programs to support tighter interaction between academia and industry are not only welcome, but necessary.
Moreover, the case is made for academic institutions, being critically involved in workforce training, to collaborate more tightly with industry on targeting, through research as well as training and educational programs, industrially relevant and in-demand skills that will allow for a more integrated and targeted approach to be developed among researchers at the academic level which can directly benefit clinical translation.
One of the biggest hurdles to commercialization of stem cell-based therapies is the manufacture, under closed and sterile conditions, of validated stem cell products. Much has been said, on this blog and elsewhere, of the various guidances issued by the FDA that touch on the manufacture of stem cell-based products. Standardization agencies have invested significant effort in consolidating manufacturing processes and efforts at harmonization are consistently under way.
Various automated, single-unit systems have appeared on the market – some more sophisticated than others. Most of these closed systems, however, still rely on significant user input.
One new initiative, backed by the European Union, is called AUTOSTEM, and brings together a consortium of academic institution alongside industrial and EU support to create a fully automated stem cell production platform.
In their own words:
AUTOSTEM is an EU H2020 project that is developing a closed, automated, sterile pipeline for large scale production of therapeutic stem cells. It will enable lower-cost, higher-quality and more consistent stem cells to be produced, ultimately helping patients to benefit from new stem cell therapies.
The project, which is led by Dr Mary Murphy of the National University of Ireland, Galway, brings together a consortium of companies and academic institutions, including the Fraunhofer Institute for Production Technology (IPT) in Aachen, the University of Cork in Ireland and UK’s Cell Therapy Catapult.
The entire stem cell production process involves no hands-on human operations. In a recent paper, published in Regenerative Medicine, by Dr. Mary Murphy at the Regenerative Medicine Institute School of Medicine at the National University of Ireland, and colleagues involved in the AUTOSTEM project, discusses the initiative, describing it as a breakthrough way to achieve large scale hMSC production at clinical grade.
This project is backed by funding from the European Union’s Horizon 2020 research and innovation program.
Similar initiatives exist closer to home. The New York Stem Cell Foundation is developing the Global Stem Cell Array, a new technology platform for the production of induced pluripotent stem cell lines in a parallel automated process. This enables the standardization to be achieved through automation of the manufacturing process. The researchers involved in the project published a paper last year in Nature Methods which gives more details on the initiative.
These efforts are the first steps – though not the only ones – to achieving automation of large scale manufacture of stem cells, which will be increasingly more critical are new therapies mature to commercial stage.
To support these new systems, more sophisticated solutions – from ancillary materials to full scale validation controls – will have to be in place in order to shift the paradigm from the current highly laborious and poorly controlled landscape to one of compliance, quality and therapeutic efficacy.
3D bioprinting is fast becoming one of the most rapidly-growing areas of tissue engineering: the influx of new research, funds, patents and companies operating in the field is contributing to it becoming a multi-billion dollar business.
While bioprinted organs are still not a reality, big steps towards making such pipe-dreams become clinical therapies are being made: an overview of the field was given in a recent opinion article published in Trends in Biotechnology by Dr. Ibrahim Ozbolat at the University of Iowa, which highlights the state of the art of the field and issues with the scale-up of functional tissue and organ constructs for transplantation.
The most commonly used bioprinting techniques include laser, inkjet or extrusion/deposition bioprinting. Out of these, inkjet-based bioprinting is the most common. While proof-of-concept studies have demonstrated simple biological systems successfully in multiple applications, the organs that have been produced from these endeavors are small and relatively simple. More complex architectures and fully vascularized systems are yet to be produced.
A recent market analysis was made by Washington, DC-basedFinnegan IP law firm on the main players in the field in terms of awarded patents for 3D bioprinting-related work. The breakdown is shown in the table below.
|3D Bioprinting Patent Assignees||June 2016|
|Wake Forest University||40|
|The University Of Texas System||22|
|Medprin Regenerative Medical Technologies Co Ltd||14|
These numbers are growing rapidly every year, as are the companies entering this field.
Where next? There is no doubt that increased funding will keep trickling into the 3D bioprinting field, particularly as more compelling technologies are emerging demonstating increasingly more complex, functionalized constructs.
In order to remain competitive, the field will have to field the same challenges that the stem cell therapy field has encountered on its road to maturity: to demonstrate fully implantable, 3D bioprinted organs, multiple contributing factors will have to fall in place on the road to market, from manufacturing through to logistics. The complexity, particularly in the case of organs such as the kidney, liver or heart – all of which require critical vascularization to maintain cell function – will be greater than anything encountered before, but the potential rewards that much more compelling.