ElevateBio

Powering the creation of cell & gene therapies at a speed the world deserves.

Manufacturing

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In all areas of biotech and pharma, there is a never-ending quest to improve the safety, potency, and effectiveness of drug therapies by harnessing the latest scientific and technological advances. Nowhere is this more evident than in the rapidly growing area of cell and gene therapy (CGT) products. These products are becoming increasingly complex as our knowledge of disease biology expands and CGT platforms evolve, offering insights for developing better CGT products and the technologies needed to make those improvements.

In vivo gene therapies provide a simple example of this evolving complexity. This approach typically begins with an adeno-associated viral (AAV) vector: a gene construct (a designed segment of DNA) is engineered into the vector, and the vector is injected directly into the patient. Each subtype (serotype) of AAV targets a different cell and / or tissue type; specific AAV vectors are therefore selected according to the target cell or tissue in the body in which the gene therapy is intended to go.

However, most AAV serotypes target tissue types beyond the gene therapy’s desired therapeutic target. For these therapies, the next level of complexity involves addressing one or both of two possible solutions: narrowing the target range of the AAV vector both by reducing its targeting for non-desirable tissues and enhancing its targeting for the desired tissue; and engineering the vector’s genetic payload for expression only in the desired cell type, so that it is not expressed in non-target tissues after delivery.

Any of these capabilities can be engineered into the viral vector. This is the present state of complexity for most in vivo gene therapies.

In contrast, the complexities are more layered for ex vivo engineered T cell or other immune cell-based therapies, which are in development for cancer and autoimmune disease. These layers include selection of a disease-specific antigen receptor; delivery of the receptor construct into the cell; other engineering to resist the immunosuppressive tumor microenvironment, to enable long term persistence and potency once transferred back to the patient; and large-scale commercial manufacturing of the cell therapy in a GMP-compliant manner.

Moreover, ongoing research in cancer has revealed the variety of mechanisms tumors use to evade the immune system. These advances point the way of improving cell therapies; but they also highlight the need for more sophisticated tools to make those improvements. The increasing interest in developing allogeneic cell therapies or in vivo engineering of antigen receptors and other components – a concept known as “in vivo cell therapy” – adds yet another layer of complexity.

A company aiming to develop and commercialize a cell therapy must address all layers of complexity to be successful. It’s certainly not easy. It’s also expensive, because most drug developers won’t have unfettered access to the full array of technologies needed to develop the product on its own. This lack of access is especially true for gene editing, a technology essential to addressing the multi-layered complexities of tomorrow’s cell therapies.

Continued advancements in the science of T cell therapies

The earliest iterations of cell therapies for cancer were autologous; that is, they began with T cells derived from the patient. The cells were either tumor-infiltrating lymphocytes (TILs), already presumed to contain some T cells specific for tumor antigens; or they were peripheral blood lymphocytes that could be stimulated with tumor antigens ex vivo to become antigen-specific. In either case, the cells were cultured and expanded to make them modestly active, without any genomic engineering or editing, then administered back to the original patient.

However, for various reasons this approach didn’t work as well as expected. It turns out that the antigen specificities of TILs found in certain tumor types, such as breast and colorectal, are poorly defined; and some TILs populations may include T cells that have immunosuppressive, rather than antitumor, activity.

The evolution of the science, from these early iterations of T cell therapies to the current state of the art, has introduced three fundamental requirements:

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The first is an antigen receptor, such as a chimeric antigen receptor (CAR) or T cell receptor (TCR), enabling the T cell to become highly specific in targeting the tumor.

For a CAR, the identification of receptor candidates is relatively straightforward: the CAR is designed and engineered to target a known tumor antigen, such as CD19 expressed on B cell cancers.

For a TCR, identification of the best receptor candidate is not always so straightforward, because the TCR is selected from the individual patient’s repertoire of T cells and the immune system’s response to cancer (and for that matter, to infection) is usually polyclonal. This means the immune system randomly generates a large set of receptor variants against tumor antigens, but not all of these variants will be tumor-specific. Instead, activation by tumor antigens selects for variants with tumor specificity – a real-time process of natural selection, in the Darwinian sense – and thus determines the repertoire of anti-tumor receptors T cells will have.

How does this polyclonal response complicate the identification of an antigen-specific TCR? The immune system may respond to, say, 10 different antigens expressed by a tumor; then, the immune system may generate 10 sets of 100,000 T cells, one set for each antigen. But among those one million T cells, some may be therapeutically beneficial while others have no effect on the cancer. The challenge lies in isolating what might be a very small number of beneficial T cells, then identifying the receptor they express that confers their antitumor activity.

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The second requirement is engineering the T cells ex vivo to introduce the selected antigen receptor.

The workhorses for delivering antigen receptor constructs such as CARs and TCRs into a cells are lentiviral vectors, not AAV vectors. This is because lentiviruses integrate into the genome of the cell, which enables long-term expression of the receptor construct and transmission of that construct to daughter cells. But lentivirus is not without its drawbacks. It is complex and expensive to manufacture: dose-for-dose, lentivirus and AAV cost about the same, but lentivirus has lower yields per batch. However, recent improvements in manufacturing technologies for lentiviral vectors are overcoming these limitations.

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The third requirement is the need for process development, analytical development and QC, and manufacturing capabilities to produce the engineered T cells under GMP conditions, in batches large enough for human therapeutic applications.

To do this at a commercial scale, a company first has to solve the manufacturing challenges of large-scale biology, which entails defining the critical quality attributes of the product through proper analytical development and QC during manufacturing scale-up. This process is significantly cost- and labor-intensive for a small biotech company to develop for one or two products, especially if they have never done so before.

This is the present level of complexity in cell therapies, but the field isn’t standing still and the landscape continues to evolve.

Tomorrow’s cell therapies depend on gene editing

The evolution of cell therapies brings up new ideas, and with them come new dimensions in functionality to maximize the cells’ effectiveness. To incorporate these functions, cell therapy innovators will need to access new technologies.

For example: it’s long been known that lentiviral vectors insert themselves at random places in the genome. But recent research has shown that insertion of an antigen receptor construct at one specific locus, instead of randomly across the genome, can result in T cells with greater potency. So, improving T cell therapies means employing an alternative to lentivirus for delivering the receptor construct – and that alternative is gene editing.

Next, a great deal is now known about how tumors, especially solid tumors, evade the immune system.

Blood cancers are more responsive to T cell therapies because the cancer cells circulate in the blood where T cells can easily find them. By contrast, solid tumors have many types of defenses – collectively known as the immunosuppressive tumor microenvironment – to keep out T cells. To get a T cell therapy past these outer defenses and into the tumor tissue, the T cell has to be engineered with some form cell trafficking – an address code, so to speak.

Even after the T cell gets past the defenses and infiltrates the tumor, the tumor can deploy countermeasures specifically designed to weaken or destroy the T cells, such as secreting the immune checkpoint protein, PD-L1. To avoid these countermeasures, the T cell needs defenses of its own, such as the deletion of the gene encoding PD-1, the receptor for PD-L1.

Lentiviral vectors cannot be engineered to deliver all of the gene constructs needed to make the foregoing changes to a T cell, precisely where they’re needed in the genome. Instead, the changes have to be made by gene editing of the T cell itself.

Similarly, allogeneic therapies – cells derived from one donor that are engineered to treat many patients – also require technology capable of making multiple edits to the genome.

The CGT space has made significant progress in developing allogeneic therapies derived from hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs), with the EMA approving the first allogeneic cell therapy in the EU in late 2022 and FDA approving the first in the U.S. in 2023. To prevent rejection and graft-versus-host disease (GvHD) in the recipient, an allogeneic T cell must be HLA-matched to the recipient. This is a tall order, given that the human genome encodes six HLA genes, each with thirty or more variants (alleles). Alternatively, GvHD risk can be reduced by using gene editing to delete the cell therapy’s TCRαβ receptor that enables T cells to distinguish “self” from “non-self” cells, or to block expression of one or more of the HLA genes.

Another wave of the future is the concept of using iPSCs to produce “universal cell therapies”, in which functional expression of the six HLA genes is prevented via knockout of B2M, a shared subunit necessary for surface expression of these molecules, effectively eliminating the risk of rejection or GvHD. The hurdle here is that clinical-grade iPSC lines – those that comply with both Good Tissue Practices (GTP) and GMP – aren’t easy to obtain or produce.

However, introducing this array of genetic changes into a single T cell with traditional CRISPR-based gene editing systems is problematic, because there is a risk of jumbling the genome and a high cost to accessing the technology.

Gene editing nucleases like Cas9 and its orthologs used in CRISPR make a double-stranded DNA break in a target gene, temporarily resulting in two chromosome segments that are readily reassembled. If the nuclease happens to make more than one double-stranded break, temporarily resulting in four chromosome segments, the odds are still good that the segments will reassemble correctly – but those odds are not 100%. Incorrect reassembly produces chromosomal abnormalities, such as translocations and inversions, that adversely affect cellular processes and can even cause diseases. This risk is associated with every edit to the cell, and so places limits to the numbers of edits per cell that Cas9 and related nucleases can safely make.

Base editing technology gets around the potential reassembly problems posed by Cas9 and orthologous nucleases. A base editing enzyme does not create a double-stranded DNA break; instead, it cuts or “nicks” one strand of DNA, then converts one nucleotide base in the target genetic sequence to another base type. Because it carries no risk of jumbling the genome, base editing allows multiple gene edits per cell – exactly what’s necessary to make T cell therapies as potent and effective as possible.

Finally, the concept of in vivo cell therapy, which involves generating CAR or TCR T cell therapies by gene editing T cells in the patient’s body, adds the latest layer of complexity. In addition to meeting all of the requirements described above, these multi-gene editing constructs must be packaged and delivered specifically to T cells in vivo – for example, by encapsulating the cargo in nanoparticles conjugated to a CD3-targeting antibody. The first in vivo cell therapy products are approaching the clinic; as a class, they may be competitive with allogeneic T cell therapies and the space could evolve quickly. In either case, the next wave of cell therapy’s future is already upon us.

Not an impasse: A solution

To recap, then: A company aiming to create the complex immune cell therapies of tomorrow will need at least five, and possibly six, key components: (1) the antigen receptor; (2) a means of delivering that receptor, preferably with gene editing instead of a lentiviral vector; (3) GMP manufacturing for commercialization; (4) GTP- and GMP-compliant iPSC lines, preferably gene edited to be “universal cells” as starting points for allogeneic cell therapies; (5) base editing technology to engineer multiple features into the cells; and (6) for in vivo cell therapies, a means of delivering the gene editing constructs to T cells in the patient.

If a company doesn’t have access to all five (or six) components – three of which involve gene editing – it won’t be able to make and commercialize an ex vivo (or in vivo) cell therapy product. This situation might appear to leave a company with an innovative cell therapy at an impasse, but this is not quite so.

ElevateBio has technology platforms for all six components: protein, AAV vector, lentiviral vector and cell engineering platforms to identify antigen receptors and deliver them into cells; a large-scale biology approach to GMP manufacturing of CGTs at our BaseCamp facility; a bank of clinical-grade, GTP- and GMP-compliant iPSC lines in development to power regenerative medicine and allogenic cell therapies; the gene editing technology for making multiple changes to cell therapies, including those derived from iPSCs; and a range of delivery vehicles, including lipid nanoparticle (LNPs), for gene editing constructs.

Life Edit Therapeutics adds a highly innovative gene editing platform to our expertise in the discovery and development of new CGTs. Life Edit’s large and diverse array of RNA-guided nucleases (RGNs) and base editors can access virtually any region of the genome and enable the entire spectrum of edits, from small insertions or deletions to rewriting DNA sequences.

By offering this complete suite of CGT technologies to its strategic partners and portfolio companies, ElevateBio aims to develop CGTs at scale in a cost-effective and efficient manner. This is at the core of “ElevateBio’s DNA”; that is to say, ElevateBio has built this into its business model for a large number of partners, thereby significantly reducing the risk and cost of CGT development and commercialization. We believe that if the industry has more gene editing tools we can “democratize” access to these essential technologies required to make the cell therapies of tomorrow – ultimately improving medicines for patients around the globe.

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First steel rising at BaseCamp Pittsburgh, June 26, 2024
Photo credit: Multivista of Western PA

What a sight and inspiration it’s been watching the first steel beams rising over the past weeks at ElevateBio’s new BaseCamp biomanufacturing facility in Pittsburgh, located in Hazelwood Green, part of the city’s Greater Hazelwood neighborhood. In partnership with the University of Pittsburgh and the Richard King Mellon Foundation, ElevateBio is building its second BaseCamp® manufacturing facility, expected to be completed in 2027. Our flagship BaseCamp facility was established on Smith Street in Waltham, Mass., in 2019.

There is something profound, even poetic, about steel beams going up in Hazelwood Green. The area along the Monongahela River once made Pittsburgh the Steel City and a major manufacturing center contributing to the war effort during World War II. Through the 1970s, Pittsburgh was a center of vitality in the American economy.

While many have bemoaned the losses in the steel industry in the decades since, Pittsburgh’s city planners and community leaders have now been welcoming new industries to Hazelwood Green, such as robotics and automation sciences, in addition to the life sciences. In some ways, Pittsburgh is an ideal city to adapt to these new industries. The local business environment fosters innovation, the city offers many of the great cultural amenities of much-larger cities — diverse theater companies, beautiful parks and gardens, stellar cuisines, a magnificent library system, and much more — and there’s a cost of living that many families find highly attractive.

In fact, Pittsburgh was recently ranked as one of the top life sciences labor markets in the U.S., with a commanding profile in training workers to participate in this growing industry. Just last year, University of Pittsburgh Greensburg opened its acclaimed Life Sciences Building, and the University of Pittsburgh Medical Center’s investment arm has pledged $1 billion to support life sciences startups.

Building Our Presence in Pittsburgh

Steel beams in place, July 3, 2024
Timelapse from ground leveling
Photo credit: Multivista of Western PA

From the beginning, ElevateBio and the University of Pittsburgh envisioned a major presence for BaseCamp in Hazelwood. In fact, BaseCamp Pittsburgh is anticipated to take occupancy of approximately 70% of the Hazelwood Green facility.

BaseCamp is ElevateBio’s one-stop shop with all of the capabilities needed to make new cell and gene therapy products a reality. Offering end-to-end capabilities, BaseCamp provides the technologies, expertise, operations, processes, and manufacturing to accelerate the development and commercialization of transformative therapies.

ElevateBio expects to fill 170 permanent full-time positions at BaseCamp Pittsburgh. For half of those jobs, post-graduate years of education are not required, and a trade-school, community college or bachelor’s degree will be sufficient. ElevateBio also has plans to implement workforce training to help build the future of high-tech biomedical manufacturing in the region. On top of this, the build-out of the facility will ensure approximately 900 construction jobs through completion.

With the steel beams rising in place in Hazelwood Green, we’re making significant progress towards the opening of our new 125,000 square foot facility, BaseCamp Pittsburgh. I am inspired by all the individuals who have gotten us to this point and am eagerly looking forward to this important chapter for ElevateBio, the University of Pittsburgh, and the city itself.

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I recently had the opportunity to join CNBC’s Fast Money after ElevateBio was recognized as a 2024 CNBC Disruptor. In that conversation, I focused on ElevateBio as a “genetic medicines foundry,” a concept I believe captures what we do, how do we it, and the specific intentions with which we designed our business model and built the company from the outset. Through this foundry model we’re advancing programs, companies, and the entire industry with a full spectrum of tools, technologies, and expertise for developing the next generation of genetic medicines.

But what exactly does it mean to be a genetic medicine foundry? And how does it apply to ElevateBio?

An innovative business model for genetic medicines

We founded ElevateBio seven-plus years ago to redefine the way we develop and manufacture therapeutics and usher in a new era of medicine powered by cell and gene therapies, also referred to as genetic medicines. Our model goes beyond the traditional roles of a contract manufacturer or a standard therapeutic biotech company. Instead, we enhance the design and manufacturing of both our internal and partnered investigational therapies by combining platform technologies – including gene editing, cellular engineering, RNA engineering, and viral and non-viral delivery vehicles – scaled manufacturing and analytical and process development expertise. These technologies reside under two complementary components of ElevateBio’s ecosystem: Life Edit and BaseCamp.

Through Life Edit, BaseCamp, and our team of industry-leading experts, ElevateBio supports biopharma partners with end-to-end capabilities to design, develop, and manufacture genetic medicines. We are the first company to build a fully integrated technology stack and end-to-end manufacturing capabilities with what I refer to as a genetic medicine foundry.

ElevateBio as a genetic medicines foundry

Generally speaking, a foundry is a one-stop-shop to create various objects or components for the manufacturing of larger, more complex products.  Two companies from the tech sector illustrate this concept.

Taiwan Semiconductor Manufacturing Company (TSMC), established in 1987 as the world’s first dedicated semiconductor foundry, applies their technology and manufacturing techniques to produce powerful microchips – and still remains a critical supplier today of chips for phones, computers, cars, and servers in our tech-driven world. Nvidia has likewise placed themselves at the center of the artificial intelligence boom, building graphics processing units (GPUs), new software, and AI models for companies to apply in their own sectors.

In a parallel way, ElevateBio applies this same foundry business model to genetic medicines, positioning ourselves as a one-stop shop and indispensable partner for cell and gene therapy companies, dedicated to propelling the entire field of genetic medicine forward.

The benefits of our foundry approach

In essence, we serve as a catalyst for innovation and collaboration. And there are three primary ways in which our foundry model enables us, with our partners, to accelerate genetic medicine development.

The primary benefit is clear: speed of development. Our robust technology stack allows partners to choose the best technology for their product or streamline the design and manufacturing process, significantly reducing the time and resources required to develop new genetic medicines. This acceleration is not only advantageous for our partners but also has far-reaching implications for patients in need of life-saving treatments.

The second is the collaborative innovation we intentionally built into ElevateBio’s structure. Internally, that structure enables collaboration across our R&D, PD, manufacturing groups and other teams of experts on the design of next-generation medicines, with our embedded technology and capabilities at the center. Externally, our teams work closely and directly with our partners to expedite the translation of scientific discoveries into tangible therapies.

The third is the greater therapeutic flexibility our approach to partnerships gives us over a traditional biotech. Through external R&D partnerships and deals, we can advance a pipeline that creates opportunities for downstream revenues. At the same time, our partnerships allow us to advance our platform technologies and de-risk our early-stage programs, giving us the ability to build an internal, wholly owned pipeline of programs where we’ve demonstrated proof of concept and the chance of clinical success has increased.

Our impact on the industry and vision for the future

Multiple industry partners are already benefitting from the integrated technologies made possible through our foundry model.

For example, our process development and manufacturing teams at BaseCamp have partnered with Abata Therapeutics for several years to accelerate the development of their cell therapy program (ABA-101) for multiple sclerosis (MS). The technologies, manufacturing capabilities, and technical expertise of BaseCamp shaved one year off Abata’s initial IND timeline, saving them significant capital on staffing and facility costs required to design and manufacture this promising therapy. Importantly for Abata, the manufacturing process developed for ABA-101 serves as a template to benefit future development programs, including their next program for Type 1 diabetes. This collaboration also represents first time anyone has shown the ability to successfully engineer, expand, and manufacture TCR-engineered Tregs in the numbers required for use as therapeutics.

Similarly, with Kyverna Therapeutics, BaseCamp successfully completed studies to support process development and clinical manufacturing using Ingenui-T, Kyverna’s proprietary three-day manufacturing process for their autologous CAR T-cell therapy program for autoimmune diseases. This achievement is monumental when we consider the tens of thousands of patients affected by autoimmune diseases, and the speed with which Kyverna can turn the patients’ own cells into therapies that targets the underlying pathology of their disease.

Additionally, industry leaders Moderna and Novo Nordisk have turned to the gene editing capabilities of our Life Edit platform to help design potentially curative in vivo gene edited therapies and base editing therapies, respectively.

These are just a few examples of the positive impact ElevateBio is having on our industry partners and the change we’re bringing to the world. For us, “genetic medicine foundry” is more than a title or an abstract concept: it reflects the entire model on which ElevateBio was established and how we’re bringing to life our mission of advancing genetic medicines with our technology and manufacturing capabilities. We believe that being a foundry is a commitment to revolutionizing healthcare through collaboration, innovation, and dedication to improving patient outcomes.

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The story of American manufacturing is complicated. For much of the 20th century, it was the driving force in the American economy, with cities like Detroit, Pittsburgh, and Cleveland serving as hubs of industry. However, in recent decades, the landscape has undergone dramatic shifts. In 1979, manufacturing hit its peak of 19.6 million jobs, representing 22% of all nonfarm employment, and it’s never fully recovered. By 2019, manufacturing represented just 9% of all nonfarm employment. While the causes of this decline are complex and multifaceted, a few key factors stand out, including global competition, technological advances, and changing economic conditions, particularly recessions.

Despite these factors, American manufacturing is not dead. At ElevateBio, we aim to be a driving force in re-imagining and re-invigorating this sector by leading the way domestically and internationally in the biomanufacturing of cell and gene therapies (CGTs).

Biomanufacturing Represents the Future

Biomanufacturing – using living cells or organisms, such as bacteria or yeast, to produce pharmaceuticals, vaccines, and even biofuels – has tremendous potential. Over the last several decades, the promise of CGTs and their potential to treat – or even cure – diseases where there are no available therapies has become increasingly clear, and investment into these highly innovative medicines has skyrocketed. But our success in scientific discovery has given rise to other challenges:

  1. Scaling production from a few million cells in a research lab to manufacturing billions of cells needed to treat patients is uniquely complex.
  2. While science and innovation have dramatically advanced the discovery and development of CGTs, biomanufacturing advancements have lagged and relied mainly on traditional modes of development or a patchwork of technologies and providers, slowing the impact on human health.
  3. Crucially, the skilled labor force needed to manufacture these life-changing medicines is limited and clustered in a few small biotech hubs. To meet patient demand, we need more highly skilled manufacturing professionals and facilities, and we need to enable access to cutting-edge CGT facilities and expertise in more regions across the country and around the globe.

A Blueprint to Revitalize American Manufacturing

In a city historically known for its iron and steel manufacturing, we think future generations will hear “Pittsburgh” and know it for something else: biomanufacturing. Pittsburgh can serve as the model for how this powerful field can both revitalize manufacturing in key regions around the U.S. and fuel access to powerful new medicines for patients domestically and abroad.

In November 2021, the Richard King Mellon Foundation awarded the University of Pittsburgh a $100 million grant to create a biomedical manufacturing center at Hazelwood Green in Pittsburgh. Hazelwood Green was once the literal and metaphorical powerhouse of the city’s Greater Hazelwood. Coupled with the sprawling Jones & Laughlin plant across the Monongahela River, that South Side mill and the former Greater Hazelwood works combined to make Pittsburgh steel a key contributor to the World War II effort. It housed munitions production during World War II and following the war, it became a rolling mill, producing 10” bar steel critical to America’s growth. The decline and eventual closing of the mill in 1999 was a significant economic blow to the neighborhood. It marked the end of one type of manufacturing in Pittsburgh and a substantial source of job creation and revenue in the region.

Pittsburgh is an ideal location in which to extend ElevateBio’s manufacturing and technology, given that it sits at the intersection of science, technology, and talent. At ElevateBio, we have created an integrated ecosystem that combines R&D platforms with current Good Manufacturing Practice (cGMP), designed to power cell and gene therapy processes, programs, and companies to their full potential. BaseCamp® is our cGMP manufacturing and process development business that offers end-to-end capabilities for our partners and internal programs. Our flagship 140,000 sq. ft. BaseCamp facility is located in Waltham, Massachusetts, and in 2022, we announced our geographic expansion to Hazelwood Green in Pittsburgh through a 30-year partnership with the University of Pittsburgh and the R.K. Mellon Foundation. Our planned BaseCamp expansion in Pittsburgh will enable an even greater number of biopharmaceutical companies, innovators, physicians, and scientists to translate revolutionary science and research from bench to bedside. At the same time, we’ll bring more than 170 permanent full-time jobs, 900 construction jobs, and 360 off-site support jobs to Pittsburgh.

Importantly, this partnership builds on Pittsburgh’s leadership position in manufacturing technologies and the University of Pittsburgh’s innovative research. The University of Pittsburgh’s nationally ranked and internationally regarded School of Medicine and research across the health sciences are a natural fit for ElevateBio — after all, this was where Jonas Salk cured polio. The unique ecosystem that makes Pittsburgh so attractive for this initiative also exists in many other formerly great manufacturing regions in the U.S., opening up the potential for growth and a roadmap for revitalizing manufacturing in the U.S.

Training the Biomanufacturing Workforce of the Future

At ElevateBio, we know that talent is key to catalyzing a new technology-driven bioeconomy in Pittsburgh and beyond. To accomplish this objective, we are working to create high-skilled jobs and train a new generation of manufacturing workers.

Here is how:

We have workforce development, local trade, and community college outreach programs to help train and develop professionals with varying levels of education.

We aim to advance careers through continuous hands-on training and professional development activities in multiple disciplines, providing opportunities for individuals changing careers and young professionals entering the job market.

We offer high-paying job opportunities to a broad spectrum of individuals that will serve them well over the lifetime of their careers, whether at ElevateBio or another company in the bioeconomy in the future.

ElevateBio is putting our expertise and our money where they count. In Pittsburgh, we estimate the cost of our hands-on training and professional development activities will be over $40 million. This includes the salary required for highly skilled trainers (Ph.D.’s.), the wages of trainees, and consumable costs per person per month, with additional resources necessary to continue talent development as new technologies and techniques emerge. An anticipated 50% of employees in Pittsburgh will have a trade school, community college, or bachelor’s degree level of education; the remainder will be industry experts and individuals with advanced degrees.

Our workforce development program focuses on our mission to power the creation of life-transforming cell and gene therapies, at a speed the world deserves; this is a key motivator for all our employees each and every day. Training is conducted in a classroom or laboratory setting where new staff can learn and ask questions to ensure they have a strong understanding of both how and why they are carrying out an activity. We provide the education and tools for individuals to be successful not only during their time in a particular role but also in different departments or other companies as their careers advance. The education that our employees receive through our programs provides them with the fundamentals of product development and in-depth training for their specific job functions.

In addition to training and continuing education, we offer competitive salaries, benefits, and leave policies to all full-time employees to attract and retain talent. We believe that through investments in a highly skilled manufacturing workforce, we can also advance the local economies in which we do business.

We’re Helping to Drive the Next American Manufacturing Revolution

Western PA is on a journey of becoming a premier U.S. biomanufacturing center: it has all of the elements necessary for success – research institutions as well as medical facilities providing clinical care, patient monitoring, and tracking of health outcomes – that are also all reasons we chose to expand into the region. Through our continued expansion and commitment to powering the field of cell and gene therapy for decades to come, ElevateBio is creating jobs, building a new generation of highly skilled manufacturing workers in America, and looking for synergies globally. Through this effort and our cutting-edge technology platforms, we are accelerating access to technologies and expertise that have the power to change the future of medicine. We’re looking for innovators and partners who want to join us in pioneering the future of CGT and the biomanufacturing economy. Come work with us as we seek to usher in the next great wave of American manufacturing.

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Lentivirus is a commonly used viral vector for delivering genes to cells, both directly in vivo and ex vivo, for engineering cells prior to infusion back into patients. Over the past twenty years, lentiviral vectors (LVVs) have been extensively optimized to improve their functional and safety features.

Building on these advances, ElevateBio has recently developed an LVV manufacturing platform, which we now offer to strategic partners through our BaseCamp facility. Compared with other available options, our platform is differentiated along two key dimensions.

The first dimension encompasses our platform’s technological capabilities and adaptability, which allows us to take solution-based approaches for producing LVV at volumes and purities that meet our partners’ needs at any stage of product development. The second encompasses holistic, end-to-end support for our LVV products, which is rooted in our team’s extensive collective experience from construct design to GMP manufacturing, and connected to ElevateBio’s other core technologies in the same facility.

Both dimensions enable our strategic partners to accelerate their development timelines, better manage costs, and, above all, transform their product development and potential for clinical success so that life-changing medicines reach the patients that need them. In addition, we have teams that offer core services to make viruses at the research level for partners, using a scaled-down platform, which provides consistency early in development and can also enable acceleration of timelines. Let’s look at these two dimensions of our LVV platform and the advantages they offer.

Going straight to suspension from the start

First and foremost, our platform produces LVV utilizing a suspension-based process, where cells are grown in 3D culture systems, instead of an adherent-based process, in which cells are grown in a 2D monolayer culture attached to a surface. Our exclusive reliance on suspension allows for process scale-up and more streamlined transitions between stages of development that an adherent process does not.

Because Phase 1 programs do not typically require large amounts of LVV, most CDMOs and academic centers that provide vectors for Phase 1 trials use an adherent process. Still, there are a number of drawbacks associated with adherent processes. One is that adherent cells typically require culture media supplementation with fetal bovine serum (FBS), which carries unnecessary safety risks and adds complexity to downstream operations. Another is that adherent processes using static vessels can only be scaled out (as opposed to scaled up) by increasing the number of vessels, which results in laborious and inconsistent manufacturing processes. Despite these drawbacks, adherent-based processes are technically simpler and require lower capital investment in laboratory equipment, and for these reasons, Phase 1 trials typically use an adherent process to produce LVV.

However, many products require suspension to produce vector quantities sufficient for later development stages, which creates potential stumbling blocks. When a company switches from an adherent to a suspension process midway through clinical development, it must demonstrate the adherent process used to generate the earlier IND-related product is comparable to the suspension process used to generate product for pivotal trials. Switching processes costs time and money; moreover, if comparability between the two processes cannot be demonstrated, the company may have to repeat the earlier clinical trials using the suspension-generated product, costing even more time and money.

Our vector team thoroughly understands the drawbacks of navigating this switch, particularly for accelerated clinical development pathways where CMC timelines are critical. This is why we were determined to build an LVV platform that utilized suspension across the board. We can produce LVV at whatever scale and purity is appropriate to the phase of development and the type of gene therapy for which the LVV is used (in vivo or ex vivo) to de-risk vector production for our partners and save them time and money later — if early-stage clinical trials prove successful. Additionally, we can offer research viruses at scales from one to 10 liters, using a representative scale-down model of the GMP process.

A second advantage is the capacity of our facility. Most companies have to reserve capacity with a supplier a year or more in advance, introducing long wait times that impede product development. With two GMP production suites for LVV now available, ElevateBio currently doesn’t have these bottlenecks. While that availability could change as our capacity fills, we plan to grow and add additional capacity according to the needs of our partners, so that they can accelerate their product development relative to competitors.

Our platform is also completely customizable to the partner’s needs. While our platform has established processes for LVV production, we are not restricted to using them. If a partner has already developed their own process or wishes to create a custom process for their specific needs, we can rapidly transfer their process or build on our platform to establish a process that meets our partner’s requirements due to our extensive in-house LVV process development expertise.

Our platform is geared towards anticipating and meeting the partner’s exact needs, wherever they may be in product development.

Unrivaled end-to-end support

Our LVV platform’s technological features are complemented by the holistic, end-to-end support our team provides for LVV-based products. We can help a partner develop a therapeutic product from idea and IND to regulatory submission and GMP manufacturing.

This seamless integration, which other providers cannot offer, is possible because our LVV platform and team don’t operate in isolation from the rest of the ElevateBio organization. Both are closely connected to ElevateBio’s other core technologies and expertise, such as assay development, cell therapy development, and vector engineering for LVV construct design.

For example, we can assess the impact of process parameters on downstream development by testing the LVV potency in target cells, such as T cells or hematopoietic stem cells (HSCs), and looking at whether a given parameter alters the final product quality and potency. We can also develop vector potency assays in the early stages of development to better understand the product and process and, ultimately, help accelerate product development timelines. These capabilities de-risk development by alerting us to PD changes that will adversely affect the product’s critical quality attributes (CQAs), so that we can avoid those changes later and by assuring the partner that our vector itself is fully compatible with their final product.

Our end-to-end support spares our partners from the “piecemeal” approach of switching vendors at each stage of development. We also save them from having to develop a process in-house for one stage, only to discover that process does not translate to the next stage of development.

ElevateBio knows that delivering end-to-end support means balancing the science and the business. From a scientific perspective, we know that investing time and money upfront – for example, in developing the scalable suspension process for LVV production – can save much more of both down the line. From a business perspective, we understand the need to keep development moving ahead: if timelines slip by even a quarter, market opportunities could be missed. By striking the right balance between the value of the science and the needs of the business, we set up each partner’s product for potential success in the clinic.

Elevating the endgame

All of the foregoing shows ElevateBio bears no resemblance to a traditional CDMO. Instead of working with a host of customers, we work with a selection of strategic partners for whom we can utilize our expertise to further their development and drive their value, just as if they were our own company. For them, it’s like joining a country club: our partners gain access to our expertise and facilities, and they get our full attention every step of the way. Our “white glove” approach translates into the value-adds of lower development risks, accelerated development timelines, and better product quality for our partners.

Most importantly, we have the experience to help partners get it “right the first time,” – which means understanding the endgame that is essential for success. Our whole organization is structured with this endgame in mind. Many ElevateBio team members have been working in the gene therapy space since its earliest days, and collectively we have expertise across the entire life cycle of product development.

Additionally, our core technologies for vectors, cell therapies, gene therapies, and gene editing are under one roof at ElevateBio, which houses facilities built to support R&D, PD, and GMP manufacturing. The combination of these elements within one organization is a tremendous asset for our strategic partners and us because they don’t have to outsource any part of their development process.

Ultimately, our unique combination of facilities and experience greatly benefits patients. We are rewarded by being part of today’s revolution in medicines that can give patients a cure and give families more time with their loved ones. The production of LVVs and the therapies that utilize them isn’t just our job; it’s our passion.

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The development of cell and gene therapies (CGTs) is highly complex and challenging. While incredible strides have been made in the field, this area of the biotech industry is still maturing, especially when it comes to manufacturing. Because we’re just starting to see the first wave of cell and gene therapies reach commercialization, managing the entire life cycle of CGT product development is still a very specialized skill.

Along with specific technical challenges of CGT process development and manufacturing, CGT life cycle management involves complex supply chains, traceability systems and analytics to guarantee safety and navigating the CGT regulatory environment. The cost of failure is also quite high in terms of additional expenditures, lost time, and patients’ lives that may hang in the balance.

All of these factors underscore the importance of correctly managing the life cycle of a CGT product the first time around, by knowing upfront what’s needed for regulatory approval and then developing the product to meet those needs from the start. But the challenges of “getting it right, right from the start” are more than just technological. Success depends on having both the right processes across the life cycle and the right people to develop and execute those processes. Having one but not the other is a recipe for failure.

Process in the CGT product life cycle

The life cycle of a CGT product starts with procurement of materials, including reagents and cells from donors or patients for autologous products, and extends through dose administration for clinical use. All along that complex supply chain, many different controls must be in place to define, characterize, test and validate the materials. A key element in the supply chain is traceability, which is the process of keeping cellular materials segregated, safe, and well identified from their sourcing through manufacturing and into the patient, and it requires very specific systems and analytics.

Traceability is especially critical for autologous cell therapies. When a patient’s blood sample comes to the manufacturing facility and the starting cells are isolated from that sample, it is necessary to ensure the right patient’s cells are modified in the right way – to generate the needed CGT – and then sent back and administered to that same patient. Lack of certainty anywhere along that chain of custody creates a major safety concern: administration of the CGT product to the wrong patient will induce an immune response (rejection) that could severely sicken the patient.

Securing the CGT chain of custody is highly important, but so are the analytics needed to identify and validate the cells along that chain. For example, in-house release testing methods for an autologous therapy must be able to correctly identify the original patient’s cells, even after they have been genetically modified. The chain of custody also includes logistical components, such as training hospital staff to receive and administer the cells.

All of these factors come into play when navigating the complex regulatory environment, which is the primary hurdle that CGT companies face, especially on the manufacturing side. A CGT company must be in constant communication with the U.S. Food and Drug Administration (FDA) to get the Agency’s input and feedback. When a company does submit an IND for an autologous CGT product, the FDA’s top questions are always, “What is your traceability matrix?” and “What is your control around the traceability for the product?”

Materials used for CGT manufacture are defined, tested and regulated very differently than materials for other drug products. Regulations for each CGT material differ among regulatory agencies around the world.

Therefore, knowing the domestic and global regulatory environment, especially from a CMC perspective, is critical to success. If the CGT team hasn’t lived this life cycle approach to CGTs and their regulation, it has to start from scratch; and without someone who has that hands-on experience, the learning curve is very steep.

The importance of getting it right the first time

In addition to managing the life cycle components described above, it’s also necessary to understand how each of those components ties into manufacturing, and how to make critical development decisions around them, early on the development of a product. Whether the issue is raw materials, developing a process or gaining regulatory approval, waiting to think about these things until the product is approaching the clinic – or even after it has completed clinical testing – makes it harder to introduce the necessary changes later.

The main regulatory hurdle for CGTs is not getting FDA to accept an IND; the agency does accept INDs based on how products have been characterized for Phase 1 testing. The real hurdle comes later, when a company has to conduct process performance qualification (PPQ), which is the characterization and validation required to produce commercial batches of CGT product.

If the PPQ hasn’t been worked out before submitting the IND and entering the clinic, then later clinical development and commercialization will be an uphill battle. The company will have to demonstrate comparability between the previous (IND-related) and newer (approval-related) processes; otherwise it will not be able to use the data generated throughout clinical development to seek regulatory approval. If comparability cannot be shown, the company may have to repeat clinical trials using the new PPQs.

In fact, one of the main reasons the FDA puts products on clinical hold relates to CMC activities or deficiencies, such as lack of comparability. Therefore, a CGT company must anticipate where its product will need to be at the commercial end of the life cycle and develop the product with those needs in mind from the outset. Doing this may involve more work on the front end of the cycle, but it ultimately results in lower costs and development burdens downstream – both of which accelerate the commercialization of the CGT product.

Building the right team

People are just as critical to successful CGT product development as the processes. If a CGT company has one but not the other, the potential for failure is high, because developing and implementing processes correctly requires a team with experience and know-how across the entire life cycle. Putting together the right team comes down to recruiting, hiring and, above all, retaining the right people.

Given that the CGT sector is still in the early stage of growth, the talent pool is quite limited, and it’s practically impossible to staff an entire company only with people who have CGT expertise. But finding the right people is achievable by viewing people’s backgrounds and experiences through the appropriate lenses rather than strictly seeking CGT experience.

To be sure, at any CGT company there are some roles where it is essential to have people with prior CGT experience in order to accelerate development. These include such roles as managing technical operations across the entire life cycle and developing the specialized electronic systems for traceability. However, there are other roles that can be filled by people who don’t have any CGT experience but do have transferable skills. The key is educating and training those people to redeploy their extensive expertise for CGT applications.

This redeployment approach can work well for many, but not all, potential CGT employees. For example, it’s hard to teach someone who has “lived” small molecules throughout their entire career how to reapply that knowledge to CGTs; whereas for people who have worked with proteins, enzymes, and antibodies, the transition to CGT comes more naturally.

In the end, the real challenge in assembling the right CGT team isn’t hiring people; it’s retaining them, because the still-limited pool of CGT is highly sought-after and competitive as the field continues to grow. Therefore, the key to keeping an experienced team on board is offering them a variety of products, projects, roles and opportunities, so that they remain happy, excited and fulfilled.

How the ElevateBio model gets it right

At ElevateBio, we have everything it takes to get CGT development and manufacturing right the first time: an infrastructure for the entire product life cycle; a world-class team of drug developers and operators who can get the job done successfully; and a diverse and growing portfolio of innovative CGT products. Having all three – infrastructure, people and product diversity – in one place benefits us in several ways.

First, because we don’t have to line up CDMOs, we can control our own timelines which saves us time and money.

Second, we have a great deal of talent under one roof; this promotes rapid knowledge transfer among team members and gives us the flexibility to assign our people to multiple products, platforms and technical areas.

Third, we anticipate our employee retention will be higher than conventional CGT companies precisely because we can offer people a wide variety of opportunities within one organization, and we believe this variety will continue to draw additional talent to us.

Together, these benefits translate into an ability to accelerate the development of affordable CGTs and deliver them to as many patients as possible.

The CGT sector continues to grow at a rapid pace. There are now many sophisticated CGT companies and a host of exciting new technologies, from electronic traceability systems to robotics, that are advancing how CGT products are developed and manufactured. However, all of the technology and automation in the world will not guarantee success without having the right processes and the right people in place across the whole life cycle of a CGT product.

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