For messenger RNA (mRNA) therapeutics and vaccines formulated as lipid nanoparticles (LNPs), the excipients receiving the most attention are the encapsulating lipids. While these compounds are crucial to the stability and delivery of mRNA-LNPs, the non-lipid excipients also play crucial roles in the function of final drug products. They impact the morphology and stability of these delivery systems, which in turn affects

performance and the overall usefulness of mRNA drugs developed using nanoparticle technology.

Non-lipid excipients used to formulate mRNA-LNP products include solvents, salts, and sugars/cryoprotectants, according to David Jung, senior manager RD&I, nucleic acids at Evonik. Overall, these excipients serve the function of controlling the pH during the initial mixing and formation of the particle and ensuring stability upon storage of the material, he notes.

More specifically, rapid mixing is the predominant technique for lipid nanoparticle–mRNA formulations: an ethanol phase (lipid components) and an aqueous phase (mRNA molecules, usually in acetate or citrate buffers) are mixed under specific conditions (pH and flow rate), explains Luca Bruno, segment marketing manager, MilliporeSigma, the Life Science business of Merck KGaA, Darmstadt, Germany. Rapid mixing, he adds, allows scalability and reproducibility of mRNA-LNP formulation.

Organic solvents and residual components are then removed by ultrafiltration. The mRNA-LNP drug substance is then formulated using a more physiological buffer, typically tris(hydroxymethyl)aminomethane- or phosphate-based together with salts such as sodium chloride or potassium chloride to adjust the ionic strength, Bruno observes.

Storage conditions (as aqueous solutions, frozen, or lyophilized) must also be carefully considered in the context of mRNA-LNP clinical translation, according to Bruno, because they can affect the long-term stability of mRNA-LNP formulations. “Sugar stabilizers (sucrose in particular, trehalose or mannitol as alternative options) are commonly used for this application,” he says.

Choosing the right non-lipid excipients important

In addition to assuring long-term stability and in vivo performance, non-lipid excipients for mRNA-LNPs also play an important role in controlling manufacturing processes, Jung comments. “The selection of these excipients must therefore be done carefully. Typically, they are initially chosen based on their chemical and physical properties (i.e., pKa and lyophilization characteristics, freezing point/state) because these attributes will determine compatibility with the drug substance. Because these choices may also impact the morphology of mRNA-LNPs, which can affect overall efficacy and stability, modifications may be required as determined [by] experimental testing,” he says.

The susceptibility of mRNA to degradation requires that formulation buffers be free of any ribonuclease contamination. Testing of excipients for the absence of nuclease activity is therefore the preferred approach, Bruno stresses. Other product-quality attributes should also be determined, including endotoxin content and bioburden, as they play an important role in controlling the risk of contamination by these materials.

Beyond the product-quality attributes, Bruno emphasizes the need to consider supplier related aspects for any excipients used in mRNA-LNPs, including non-lipid excipients. “Supply robustness and availability of supporting documentation are both essential if mRNA-LNP developers are to navigate regulatory challenges and ensure smooth manufacturing scale up and progression through clinical development to commercialization,” he adds.

Since the approval of the COVID-19 mRNA vaccines and demonstration of their effectiveness, interest in mRNA-LNP therapeutics and vaccines has risen dramatically from all perspectives. In particular, the rise of the mRNA technology due to the COVID-19 pandemic and the manufacturing scale needed to produce vaccines shifted the attention to mRNA manufacturing needs, according to Bruno.

“The development of non-lipid excipients has primarily focused on the quality attributes based on the specificity of the technology,” Bruno notes. For instance, the need for endonuclease-free materials required establishment of additional product-release testing methods and services to support drug manufacturers.

There has also been a significant amount of effort placed on assessing non-lipid excipients that may improve the long-term stability of mRNA-LNP formulations, observes Jung. He points specifically to the use of different cryoprotectants to improve refrigerated storage stability. Lyophilization is also being explored as a means for eliminating cold-chain requirements, with several clinical-stage studies underway to assess the impact of lyophilization on the stability and in vivo efficacy of traditional mRNA-LNPs.

Separate efforts are also underway to create novel delivery mechanisms for RNAs that are not dependent upon LNPs, Jung adds.

A key focus in the mRNA field is on lipid excipients and that will continue to be true for some time, contends Aditi Mehta, head of mRNA process and delivery, MilliporeSigma, the Life Science business of Merck KGaA, Darmstadt, Germany. “Despite the success of the COVID-19 vaccines, we still have not reached the full potential of mRNA therapeutics, and there are several hurdles. Insufficient targeting of organs beyond the liver or vaccinations, an acute immune response against LNP administration, stability issues, and the need of extreme low temperature for storage are key bottlenecks in the development of LNP medicines,” she says.

These issues, Mehta observes, can be addressed through improvements in lipid and LNP design, (e.g., optimization of linker chemistry, addition of degradable bonds, more optimal synthetic routes, better LNP components, etc.). “Strategies such as design of novel ionizable lipids based on large libraries produced with combinatorial synthesis have been aiding the understanding of structure-function properties and enabling the design of unique lipids with improved properties (targeting, stability, tolerability),” she states.

Data continues to be published on new lipid libraries that demonstrate delivery to different tissues/cells (1), Jung agrees. Targeting of mRNA-LNPs to specific tissues or cells can be achieved through either passive or active means. A majority of studies investigating ways to target LNPs have focused on passive targeting through modification of the LNP size, surface, and composition. Substitution or addition of an extra moiety (polymeric or lipidic) has also been shown to be beneficial for achieving passive targeting toward specific organs, according to Mehta.

“Active targeting approaches leverage conjugation of lipid components with small molecules, antibodies, proteins, or aptamers,” Mehta comments. She points specifically to flexible platforms and highlights the ASSET platform developed in the lab of Prof. Dan Peer at Tel Aviv University (2). “This type of approach enables customized targeting towards any cell receptor and, therefore, any tissue or organ,” she says.

Mehta does caution, however, that while there has been a tremendous push (and success) in this area over the past few years, there is still a long way to go and many challenges to overcome.

While lipids have predominated the mRNA delivery space, they are not the only materials that can provide effective delivery of these sensitive and highly charged drug substances. Hybrid lipid–polymer delivery systems, for instance, have been developed to harness and combine the advantages of both lipid and polymer nanoparticles, according to Mehta.

“Polymers possess an inherent high degree of chemical variety that is not feasible with lipids, increasing tremendously the possibilities of chemical functions, such as promoting endosomal escape, controlled released of RNA, targeting, and finally stability,” she explains. Lipids, meanwhile, show great potential for enhancing bioavailability, improving pharmacokinetic profiles, and increasing biocompatibility.

Strategies investigated to formulate hybrid systems include lipopolyplexes, hybrid LNPs, and others. As an example, Mehta notes that incorporation of biodegradable polymers such as poly(beta amino esters) in LNP formulations leads to improved and specific lung delivery, highlighting the potential of hybrid lipid-polymer nanoparticles (3).

Evonik has a research agreement with Stanford University to develop and commercialize the charge-altering releasable transporter (CARTs) technology initially developed by the Waymouth lab. These polymeric materials can effectively encapsulate mRNA and then rapidly degrade through controlled self-immolative reaction to release the mRNA, according to Jung.

“The first generation of CARTs showed mRNA delivery efficacy in a range of cell types in both in vitro and in vivo models,” Jung notes. He adds that subsequent generations of CARTs incorporating lipid side chains on the CART backbone structure (4) showed an improved delivery efficiency.Further generations of CARTs that are still under development, says Jung, have shown specific targeting capabilities in preliminary testing (5,6).

Kularatne, R.N.; Crist, R.M.; Stern, S.T. The Future of Tissue-Targeted Lipid Nanoparticle-Mediated Nucleic Acid Delivery. 

Kedmi, R.; Veiga, N; Ramishetti, S. Goldsmith, M.; Rosenblum, R. et al. A Modular Platform for Targeted RNAi Therapeutics. 

https://doi.org/10.1038/s41565-017-0043-5. https://www.nature.com/articles/s41565-017-0043-5

Yan Cao; Zongxing He; Qimingxing Chen; Xiaoyan He; Lili Su, et al. Helper-Polymer Based Five-Element Nanoparticles (FNPs) for Lung-Specific mRNA Delivery with Long-Term Stability after Lyophilization. 

https://doi.org/10.1021/acs.nanolett.2c01784. https://pubs.acs.org/doi/10.1021/acs.nanolett.2c01784

McKinlay, C.J.; Vargas, J.R.; Blake, T.R.; and Waymouth, R.M. Charge-altering Releasable Transporters (CARTs) for the Delivery and Release of mRNA in Living Animals, 

McKinlay, C.J.; Benner, N.L.; Haabeth, O.A; and Wender, P.A. Enhanced mRNA Delivery into Lymphocytes Enabled by Lipid-varied Libraries of Charge-altering Releasable Transporters, 

Haabeth, O. A. W.; Lohmeyer, J. J. K.; Sallets, A.; Blake, T.R.; Sagiv-Barfi, I. et al. An mRNA SARS-CoV-2 Vaccine Employing Charge-Altering Releasable Transporters with a TLR-9 Agonist Induces Neutralizing Antibodies and T Cell Memory. 

 2021 7 (7), 1191-1204 DOI:10.1021/acscentsci.1c00361

Cynthia A. Challener, PhD has been a freelance technical writer for over 20 years and contributes regularly to 

Articles

Features

Stability and in vivo performance aren't just affected by lipids.

The Impact of Excipients on Stability in mRNA-LNP Formulations

Therapeutic biologics are thriving, according to Zhou Jiang, director Cell Culture Services at Cytiva. “As we work to advance the next generation of therapeutics, we must address these challenges to deliver the medicines patients need. The increasing diversity introduces new challenges and mandates new solutions in upstream cell culture,” says Jiang.

Gary McAuslan, CEO aCGT Vector, outlines some central challenges, stating, “cell therapy manufacturing today is unsophisticated and in the main, extremely manual and people dependent, shocking from a microbiological contamination potential, and impossible to scale in a controlled manner from a mass uptake of precision medicines perspective. Batch failures, low viability, and time to patient exceeding the patient’s life expectancy are the stark realities of today’s pharmaceutical manufacturing response that attempts to bulk manufacture what are truly individual modern medicines at a scale of N=1."

“Only one of the CAR-T innovators ship fresh patient T-Cells for good reason,” he says. McAuslan concludes. The current default, for example, for the first CAR [chimeric antigen receptors]-T Kymriah from Novartis is to use frozen T-cells that are collected at the hospital from a patient, sent across the world frozen, thawed, cell engineered, frozen again, shipped again and thawed again, before being administered inside the same hospital over a month later, taking just 11 minutes to infuse into the same patient. The current logistical complexity is restricting cancer patient access to the just 15,000 treated since the first approval in 2017 versus the projected annual 2 million patients who might benefit from CAR-T treatment. Pharma can absolutely do better than this. Both of these therapies are manufactured and shipped back frozen, a number of weeks to an individual patient for administration inside a hospital center of excellence approved to do so. Being able to eliminate these complex logistics, and time especially (in the region of 27% of patients die waiting on their own CAR-T therapy), as a complementary manufacturing supply chain will increase access substantially.”

This need for speed comes in parallel, but case by case, when compared with the warp speed efforts during COVID-19 vaccine development and deployment programs. Jiang reflects on this phase, saying, “There is also the drive to produce the highest possible titers with the best product quality, which has led to efforts to produce more robust cell lines and media formulations suitable for a wide variety of cell lines and biopharmaceutical molecules. Insights from the cell biology of CHO [Chinese hamster ovary] cells, and understanding of the relationships between specific metabolites and cell culture outputs such as titer and quality are highly valued and sought after for the realization of these goals.” This is why so much research, investment, and time has been focused on advanced therapy medicinal products (ATMPs) in the past few years.

From a drug-development and clinical perspective, analytical characterization of material is important at every step, and making sure the critical quality attributes (CQA) stay within a threshold, within specifications and guidance, are chemistry, manufacturing, and controls (CMC) issues, which need to be tackled during the early manufacturing process development. Vibha Jawa, head of Biotherapeutics Bioanalysis in Nonclinical Disposition and Bioanalysis (NDB) organization, at Bristol Myers Squibb, points to this saying, “further, we are always quantitating transduction efficiency and target response ... titer quantitation helps us to visualize the transgene expressions in a much more reliable and specific manner whether we are looking to quantitate what that transgene expression is, or whether we are looking to characterize and optimize the amount of the vector we are going to administer. This is because a lot [of] safety and toxicity challenges turn out to be proportional to the amount of the virus used, and the content of that virus from an empty versus full capsids perspective. The best case option for the patient is to have the highest does load presented via the least virus delivery method possible.” Sometimes poor results or failure here even precludes proceeding with the originally intended ATMP plan. Sometimes caregivers revert to antibody drug conjugates or other well-understood treatments, as the novel medicines are sometimes simply not the best choice option for that patient.

The closer one gets to the situation in the clinic, the more these challenges stand out in stark relief. Jawa relates that groups have been struggling to get sufficient well-characterized material for clinical studies. “Even if you have plans to file an IND [investigational new drug application], unless you have a good contract development and manufacturing organization (CDMO) ready with that kind of capacity waiting for you, you have to be able to synchronize with their timelines, because they are busy making someone else’s viral vector. So you have to put yourself into that que,” she states, referencing the need to always be cognizant of many other people’s timelines. Jawa goes on to say, “because there are very few of them [CDMOs] that are good and reliable. And you really need material that is the least toxic in terms of residual or process-derived contaminants, but is effective to get your transgene in, and is a good drug product within that viral vector.”

Another logistics and business challenge, according to Jawa, is which patient cohort one is working with. “It’s a highly competitive situation, especially if you are targeting diseases which affect large numbers of patients. For rare disease states, there is no such resource pressure, and the landscape is not as [potentially] crowded with competitors ahead of you making these vectors.”

Near patient manufacturing small footprint systems combined with increased automation seem to be where much of the current progress has been made. Baley Reeves, interim director at the National Center for Therapeutics Manufacturing, points out that, especially for small footprint systems, “with scaled-down/scale-out operations, quality control and regulatory [issues] are more difficult hurdles to manage. Automation and inline analytics become even more critical pieces of the process. This mainly impacts autologous cell therapies at the moment but could have future implications as personalized medicine takes off,” she suggests.

Common issues to achieving high titer levels are manufacturing plasmids that contain difficult genetic payloads (e.g., gene-of-interest size, base composition, toxicity, use of selection markers). When pursuing large plasmid sizes to navigate those challenges, one is then often confronted by leaky promoters that lead to pre-mature protein expression upstream, losses during alkaline lysis or repeated sequences such as inverted terminal repeats (ITR) and polyA tails that are more prone to deletion and recombination events. Some successful ways to navigate these obstacles are to optimize and balance buffer volumes, be more precise in terms of buffer contact times. By using more gentle mixing methods, one can reduce sheer impacts. And of course, it always helps to start with well-characterized pHelper and pREPCAP plasmids. Viral vector synthesis network Helper plasmid (pHelper) activates expression of the rep/cap gene on the packaging plasmid (pPackaging) and synthesis (k Cap_syn and k Rep_syn ) of viral protein (VP) and Rep protein (RepProtein). “Capsid proteins are assembled (k assembly) into empty capsids in the nucleus (EmptyCapNuc), and each capsid particle consists of 60 protein subunits. With helper functions from the helper plasmid, the Rep protein replicates (k DNA_rep) viral DNA (vDNA) from the transgene vector plasmid (pVector)” (1).

A key to knowledge transfer may depend on reimbursement model modifications, and regulators embracing the idea of “equivalent centers,” leading to standardizing some equipment and protocols. aCGT Vector, for example, has concentrated on “right-size pharma—standardized, automated, and closed-system technology and expertise ... truly end-to-end services offering, that can increase access for innovators and patients alike. For example, Janssen with their CARTITUDE front-line defense for the most common blood cancer, multiple myeloma. Novartis also recently secured reimbursement by the National Health Service (NHS) in the United Kingdom for earlier treatment of their cancer treatment. In time as these precise targeted but individual treatments are demonstrated as a better use of healthcare budgets, the predictions point to locally distributed centers complementing large centralized facilities, where a patient can walk into their hospital, receive CAR-T treatment, and go home days later, with the hope of potentially surviving their own cancer. Excitingly, the rare disease landscape, where many of the 7000 untreatable diseases such as blood cancer, is changing and bringing hope to patients and their families,” says McAuslan.

Nguyen, T. et al. Mechanistic Model for Production of Recombinant Adeno-associated Virus via Triple Transfection of HEK293 Cells. 

Lives are saved when time from vein to vein decreases.

Therapeutic Biologics and the Need for Speed

Lonza announced on April 4, 2023 an agreement with ABL Bio, a Korean biologics company with a focus on bispecific antibodies for immune-oncology and neurodegenerative diseases. The collaboration agreement between the two companies supports the development and manufacturing of ABL Bio’s new bispecific antibody product.

Under the agreement, Lonza will provide ABL Bio with an end-to-end solution and an integrated offering to support the bispecific antibody candidate from DNA to potential investigational new drug (IND) application. ABL Bio will also gain access to Lonza’s DNA-to-IND program, which is designed to support biotech companies in realizing the full potential of bispecific drug candidates, accelerating their path to clinic and developing a robust and scalable manufacturing process.

“With the biologics pipeline evolving towards more complex protein formats, bi- and multi-specific molecules are a growing part of Lonza’s portfolio,” said Jean-Christophe Hyvert, president of biologics, Lonza, in a company press release. “For more than 35 years, our teams have built extensive experience and capabilities in this area, and we are committed to supporting our customers on their unique journey to IND. This collaboration will provide ABL Bio with greater flexibility and speed on the path to commercialization. We look forward to working together to bring this innovative therapeutic antibody candidate one step closer to patients.”

News

Lonza and ABL Bio are collaborating on the development and manufacture of bispecific antibody product. 

Lonza and ABL Bio Collaborate on Bispecific Antibody Product

Roche announced on March 22, 2023 that it has entered into a collaboration with Eli Lilly to support the development of Roche’s Elecsys Amyloid Plasma Panel (EAPP), a blood test that aims to facilitate the earlier diagnosis of Alzheimer’s disease.

The EAPP is currently undergoing additional investigation to ensure clinical validation. The collaboration aims to support patients by improving the journey to a timely and accurate diagnosis and treatment of Alzheimer’s. If approved, the EAPP test would be an additional tool to identify low likelihood of amyloid pathology in symptomatic patients and determining whether further evaluation and testing may confirm a diagnosis.

According to a company press release, up to 75% of people living with the symptoms of Alzheimer’s do not have a diagnosis. Those who have received a diagnosis waited, on average, 2.8 years after symptom onset (1). The EAPP would be used as a tool to enable access to appropriate new therapies as they become available.

“We are excited to be collaborating with Lilly on such an important area of unmet medical need,” said Matt Sause, CEO of Roche Diagnostics, in the release. “Today, over 55 million people are living with dementia, and this is projected to increase to nearly 140 million by 20502. Collaboration is essential to ensure these people receive a timely and accurate diagnosis. The Elecsys Amyloid Plasma Panel has the potential to streamline a person's journey to diagnosis and, therefore, access to future treatment options.”

1. Johns Hopkins. Life Expectancy Following Diagnosis of Alzheimer’s Disease Depends on Age at Diagnosis. Johns Hopkins Bloomberg School of Public Health. Nov. 18, 2002. 

New Technology

Roche and Lilly will collaborate on the development of Roche Diagnostics’ Elecsys Amyloid Plasma Panel.

Roche Collaborates with Lilly to Enhance Early Diagnosis of Alzheimer’s Disease 

Moderna announced on March 23, 2023 a collaboration with Generation Bio, a biotechnology company innovating genetic medicines for people living with rare and prevalent diseases, to combine Moderna’s biological and technical expertise with core technologies of Generation Bio’s non-viral genetic medicine platform. The collaboration aims to expand the application of each company’s technology by developing novel nucleic acid therapeutics, including those capable of reaching immune cells, to accelerate their respective pipelines of non-viral genetic medicines. Moderna will fund all research and development activities under the collaboration.

Under the agreement, Generation Bio will receive a $40 million upfront cash payment, a pre-payment of research funding, plus a $36 million equity investment from Moderna, with the potential for additional milestones, fees, and royalties. Moderna has also acquired an option to license Generation Bio’s cell-targeted lipid nanoparticle (ctLNP) and close-ended DNA (ceDNA) technology for two immune cell programs and two liver programs, with an additional option for a third immune cell or liver program.

"Moderna continues to invest in innovative technology to enable us to develop a breadth of transformative medicines for patients," said Rose Loughlin, Moderna's senior vice-president for research and early development, in a company press release. "Through this collaboration, which builds on Generation Bio's non-viral genetic medicines platform, we have the potential to target immune cells with diverse nucleic acid cargos and the liver for gene replacement. We are excited to have Generation Bio as our partner as we continue to broaden our therapeutic pipeline and extend the potential benefit of nucleic acid therapeutics to more patients."

"Non-viral DNA therapeutics may offer durable, redosable, titratable genetic medicines to patients suffering from rare and prevalent diseases on a global scale," said Phillip Samayoa, chief strategy officer of Generation Bio, in the release. "This collaboration represents a foundational investment in our platform science, both deepening our pipeline of rare and prevalent liver disease programs beyond hemophilia A and accelerating our work to reach outside of the liver with nucleic acid therapies. We are thrilled to collaborate with Moderna to extend genetic medicines to new tissues and cell types through the joint development of noveltargeting for our stealth ctLNPs to reach immune cells."

Moderna and Generation Bio have announced a strategic collaboration to develop non-viral genetic medicines. 

Moderna and Generation Bio Announce Strategic Collaboration

On March 22, 2023, Invitae, a US-based medical genetics company, and Deerfield Management, a US-based healthcare investment firm, announced that they are partnering to advance genetics-based drug discovery and development in rare diseases. Under the agreement, the partnership will harness genetics and clinical data from millions of patients and apply that data to Deerfield's drug discovery and development expertise.

The two parties aim to address research gaps in the drug discovery process by drawing insights from Invitae's data platform. The platform includes sizable cohorts of rare disease patients. Through collaboration, the companies will analyze data from the more than 3.6 million genetic tests delivered by Invitae that are linked to longitudinal clinical data, which will strictly follow patients' preferences for sharing of their data. The companies believe that by combining Invitae’s data with Deerfield’s analytics expertise, they will be well-suited to uncover insights needed to discover and validate new rare disease targets, according to a company press release.

"Invitae's core objectives include expanding access to genetic information to improve healthcare for patients. Through this partnership, we intend to serve millions of families affected by rare diseases with high unmet needs," said Farid Vij, general manager of patient network and data at Invitae, in the release. "Our genetic and clinical data platform is highly enriched with patients possessing rare disorders, enabling a deeper understanding of the natural history and genetic basis of these diseases, and improving the success rate of new clinical programs."

"Despite significant research efforts, there are thousands of rare diseases without a line of sight toward a viable therapeutic intervention," said Matt Nelson, head of genetics and genomics at Deerfield Management, in the release. "Invitae's unique data and analytics capabilities position it to interrogate genetic effects on rare and many other diseases. With Deerfield's extensive experience in rare diseases and drug discovery, we believe there is strong potential for this partnership to uncover valuable patient insights and create important therapies for a range of currently untreatable conditions."

Under a new partnership, Invitae and Deerfield Management will harness genetic and clinical testing data from patients to discover potential novel therapeutics for treating rare diseases.

Invitae and Deerfield Management Team Up on Novel Therapeutics for Rare Diseases

Alpha Teknova, a US-based producer of critical reagents, and Sartorius BIA Separations, a part of Sartorius, announced a collaboration on March 15, 2023 under which the two companies will aid gene therapy companies to streamline the downstream purification process, specifically for the recovery of adeno-associated virus (AAV) capsids.

Under the collaboration, Sartorius BIA Separations will combine its proprietary AAV platform, which is designed to optimize the separation of viral particles, with Teknova’s custom, high-quality buffer solutions, which have been developed to maximize capsid enrichment. The companies have conducted a robust design of experiment and have successfully created a screening kit with optimized buffer formulations, according to a company press release. The optimized buffer formulations drive consistency and increased purity when they are paired with Sartorius BIA Separations’ AAV platform (BIA CIMmultus QA monolith).

Through the collaboration, gene therapy companies focusing on AAV will get access to all required consumables as well as a protocol that will streamline and accelerate the downstream processing workflow. According to the company press release, this advantage will enable these gene therapy companies to discover novel breakthroughs faster. Teknova and Sartorius BIA Separations intend to continue developing data that demonstrate the improvements in AAV purification that result from their combined methods.

“Through our collaboration, we’re finding new tools to help our customers streamline the development of AAV therapies by optimizing their purification process and increasing the yield and purity of their AAV product,” said Stephen Gunstream, Teknova’s president and CEO, in the release.

“Teknova is the perfect partner for us as we explore robust, end-to-end solutions for our gene therapy customers seeking to achieve better results in the separation and analysis of viral particles,” said Aleš Štrancar, managing director at Sartorius BIA Separations, in the release. “Based on their ability to quickly manufacture high-quality, custom buffers that are consistent from batch to batch, we’ve been able to reliably reproduce results and confidently target the discreet differences in empty and full AAV particles.”

Sartorius BIA Separations and Teknova will collaborate to combine their technologies in an effort to streamline the downstream purification process.

Sartorius and Teknova Team Up for Gene Therapy Process Development

Polyplus, a French provider of solutions for advanced biologic and cell and gene therapy production, announced a novel cationic lipid nanoparticle (LNP) formulation for messenger RNA (mRNA) therapeutic and vaccine development on March 14, 2023. Set for release in April 2023, the LipidBrick IM21.7c is a formulation designed to expand the scope of LNP usage in various therapeutic and oncology applications, as well as prophylactic vaccines.

The formulation is designed to overcome current-generation ionizable lipid challenges used in current LNPs by enabling a wider 

biodistribution and decreasing accumulation in the liver. According to a company press release, proof of concept work demonstrated that it successfully modulates the overall charge of LNPs, improving drug efficiency and formulation stability with no additional safety concerns.

“Polyplus draws on over 20 years legacy in cationic polymer and lipid-based delivery systems for both 

 models to power mRNA therapeutics,” said Mario Philips, CEO, Polyplus, in the release. “As we carry forward this legacy, we are working to ensure that our offer opens new possibilities to improve LNP formulation to meet the growing demand of the mRNA therapeutic market. LipidBrick IM21.7c is already used in jetMESSENGER and liposomal formulations for mRNA delivery, as a ready-to-use solution that requires no onsite formulation.”

Polyplus’ LipidBrick is designed to expand the scope of lipid nanoparticle formulation usage in mRNA therapeutics and vaccine development.

Polyplus Introduces Novel LNP Formulation for Use in mRNA Therapeutics

Evotec announced on March 16, 2023 that there has been progress within its strategic partnership with Bristol Myers Squibb (BMS) relating to building a molecular glue-based pipeline. Performance-based and program-based achievements will total $75 million to Evotec.

The companies entered their strategic protein degradation partnership in 2018 and expanded it in May 2022. Evotec has scaled up its activities to develop compounds from Bristol Myers Squibb’s library of cereblon E3 ligase modulators since the expansion. The partnership’s goal is to develop high-value targets in the field of oncology and more by building a pipeline of novel molecular glue degraders. According to a company press release, molecular glue degraders are compounds that induce interactions between an E3 ubiquitin ligase and a molecular target, which results in ubiquitination and subsequent degradation of the protein. The molecular glue itself is not degraded in the process, meaning it can trigger the degradation process several times over, which can lead to longer-lasting therapeutic effects.

“The recent extension and expansion of our partnership with BMS continues to deliver high value programs,” said Cord Dohrmann, chief scientific officer of Evotec, in a company press release. “Our Omics-based, highly systematic, and industrialized approach to identify very promising molecular glues continually exceeds all expectations and will translate into an extraordinary pipeline of first-in-class product opportunities.”

Evotec and Bristol Myers Squibb have announced progress in their strategic protein degradation partnership. 

Evotec and Bristol Myers Squibb Progress Strategic Partnership

Cancer Research Horizons announced on March 17, 2023 that it has partnered with Predictive Oncology to drive the development of oncology drugs. The collaboration will use Predictive Oncology’s PEDAL artificial intelligence and machine learning platform technology to determine which cancer types and patient populations are most likely to respond to treatment with Cancer Research Horizon’s pre-clinical drug inhibitors of glutaminase. By addressing tumor heterogeneity during pre-clinical stages, the probability of clinical success increases, according to Predictive Oncology.

The agreement joins together non-profit and industry and offers the potential for Cancer Research Horizons to incorporate PEDAL technology into future drug discovery processes.

“Our collaboration with Cancer Research Horizons represents a fundamental shift in drug discovery that could lead to the accelerated development of cancer therapies using compounds originating from the CRUK network and developed by Cancer Research Horizons in partnership with their global network,” said Raymond F. Vennare, CEO of Predictive Oncology, in a company press release. “We now have the ability to impact the most critical stage of early drug discovery in a way that has never been done before.”

“We are committed to working closely with scientists to discover and advance therapies that can help in the fight against cancer. Ensuring that patients receive the right treatment for them is of paramount importance and is why we are excited to work with Predictive Oncology to identify the most suitable population for the further development of our compounds. We look forward to applying Predictive Oncology’s expertise, enabling technology and dedication to progress exciting cancer therapeutics,” explained Tony Hickson, chief business officer for Cancer Research UK and Cancer Research Horizons, in the release. “We consider the potential of this collaboration a win for patients not just in the UK or US, but worldwide.”

Predictive Oncology and Cancer Research Horizons have partnered to pursue development of cancer drugs utilizing the PEDAL platform.

Predictive Oncology and Cancer Research Horizons Partner for Cancer Drug Development

Genuv, a South Korean-based clinical-stage biotechnology company, announced on March 15, 2023 that it has entered into a partnership with South Korea-based biopharmaceutical company Celltrion to jointly discover and develop novel therapeutic antibodies. Under the agreement, the companies will use Genuv's proprietary SHINE MOUSE platform.

According to the agreement, Genuv will conduct antibody discovery services using its mouse platform technology. Drug discovery will be followed by a research collaboration. Celltrion has the option for joint research and development projects that, if exercised, will trigger agreed-upon milestones, which include development milestones of up to $25 million followed by total commercial milestones of up to $680 million. The latter amount will be triggered dependent upon the accumulation of $7.5 billion in sales per candidate antibody.

The advantage that the SHINE MOUSE platform offers rests in the platform’s ability to generate a greater diversity of antibodies than conventional mice can generate. This ability led to the discovery of the experimental, novel anti-programmed cell death protein 1 monoclonal antibody, GNUV201. GNUV201 holds unique features, such as exceptional interspecies cross-reactivity and binding affinity, which allows for preclinical disease animal model studies that have increased clinical relevance, according to a company press release.

Genuv is also developing GNUV205, an improved interleukin-2-based immunocytokine anticancer drug that is made tumor-specific by leveraging the properties of GNUV201.

“We are excited to embark on our mouse platform business with Celltrion as our first partner,” said Sungho Han, founder and CEO of Genuv, in the press release. “We believe Celltrion's in-depth knowledge and experiences in antibody development and production and Genuv's expertise in novel antibody discovery with our SHINE MOUSE platform could generate great synergies in providing innovative antibody therapeutics.”

“Celltrion is continuously interested in antibody-based new drugs and anticipates to discover differentiated antibodies through innovative antibody discovery platform technology. We look forward to partnering with Genuv for the development of innovative antibody therapeutics that will bring new hope to patients with high unmet needs,” said Kisung Kwon, head of the R&D unit of Celltrion, in the release.

The collaboration between Genuv and Celltrion will utilize Genuv's proprietary mouse platform for antibody discovery.

BioPharm International's BP Elements, April 2023