Since the first FDA approval in 2017, chimeric antigen receptor T-cell (CAR-T) therapy has garnered excitement as a potentially curative option for hard-to-treat blood cancers (1). In this therapy, T cells are genetically engineered to recognize specific tumor-surface antigens. When the engineered T cells encounter the target antigen, they proliferate and coordinate an immune response to destroy the cells expressing that antigen. There are six approved CAR-T therapies in the United States that target blood cancers. These “autologous” treatments are manufactured from T cells obtained from the patient and are genetically engineered to express a CAR that recognizes an antigen specific to the patient’s blood cancer.

When CAR-T therapy works well, it puts patients with malignant, lethal blood cancers into long-term remission. However, approved CAR-T therapies remain ineffective for many patients, and no CAR-T therapies have been successfully developed for solid tumors (2). The high cost, clinical complexity, and dangerous side effects of existing CAR-T therapies have further limited the application of an otherwise exciting and novel treatment.

Significant obstacles remain before CAR-T therapies can be adopted to treat solid tumors. Persistent efforts to expand CAR-T therapies to solid tumors are focused on identifying solid tumor-specific antigens for CAR T to target, enabling the therapy to penetrate solid tumors and ensuring that the therapy persists and functions in the immunosuppressive microenvironment of the solid tumor.

Because the immune system uses antigens to identify targets, antigens are a key factor in the development of CAR-T cell therapies. To minimize off-target effects, an appropriate antigen target for a CAR-T therapy must be present on cancer cells but not significantly on healthy cells. If a patient receives CAR-T therapy that targets an antigen present on both tumor cells and healthy tissue, the subsequent immune response may attack normal cells and has the potential to generate difficult-to-manage serious side effects.

All FDA-approved CAR-T therapies target either CD19 or B-cell maturation antigen, which are antigens associated with cell development that are highly expressed on blood cancer cells but are only limitedly expressed on healthy cells. While CAR-T therapy for blood cancers has a few clear antigen targets, identifying antigen targets for solid tumors has proved much more complicated.

Solid tumors have a wider array of potential targets than blood cancers, and the antigens expressed on solid tumors are often also found at low levels on normal cells. The overlap in antigen expression between tumor cells and healthy tissue has led to severe toxicity in early solid-tumor CAR-T therapy clinical trials, despite promising results in earlier animal models. Along with the judicious selection of antigen targets, an important parameter for the clinical success of CAR-T therapy will be the development of animal models that better represent the human immune system and the differential expression of the target antigen.

The challenge of selecting a target antigen is compounded by the heterogeneity of antigen expression in solid tumors. This heterogeneity is likely one important reason for the diminished initial and durable CAR T response (3). Heterogeneous expression means that some tumor cells may express an antigen more strongly than others, and some may not express that antigen at all. A CAR-T therapy targeting a cancer-specific antigen that was heterogeneously expressed would miss tumor cells not expressing that antigen and would be less effective on cells weakly expressing that target.

One proposed approach to circumvent the lack of cancer-specific, consistently expressed antigens on solid tumors is engineering CAR T that can identify multiple targets. This could be achieved by genetically engineering multiple CARs into the same T cell or engineering a receptor that would recognize more than one target antigen. However, multi-target CAR Ts can carry an elevated risk of severe side effects from off-target effects (4).

Individual antigens for targeting solid tumors are also under investigation. Cancers sometimes express embryonic genes, such as CLDN6, which are silenced after birth (5). CLDN6, which enables cancers to metastasize, is present in most testicular cancers, as well as in some ovarian, non-small cell lung, gastric, breast, and endometrial cancers. Still, targeting CLDN6 carries some danger of off-target effects, as the protein is expressed at low levels in the pancreas and liver, and a protein with a similar structure, CLDN9, is expressed throughout the body.

A 2022 Phase I/IIa trial of CLDN6-directed CAR-T therapy, called BNT211-01, displayed one of the first examples of CAR T efficacy in solid tumors (6). Initial trial results reported tumor shrinkage in 33% of 21 patients with seven different tumor types, including one testicular cancer patient who went into complete remission. Two additional solid-tumor targets have also shown preliminary promise in clinical trials: a study treating glioblastoma with interleukin 13 receptor subunit alpha 2 (IL13Ra2)-directed CAR-T cells and CAR-T cells targeting prostate stem cell antigen for prostate cancer (7,8).

To attack solid tumors, CAR-T cells must first migrate from blood vessels to the tumor tissue. Then, they must be able to infiltrate and proliferate in the tumor microenvironment. This cell movement is challenging for a number of reasons. For instance, physical barriers, including the extracellular matrix and the vasculature surrounding a solid tumor, make it difficult for CAR-T therapies to penetrate the tumor. Once CAR-T cells penetrate the tumor, the therapy must overcome an immunosuppressive tumor microenvironment that impairs its function and efficacy.

Many strategies for migrating to and functioning within the solid tumor microenvironment are in development, and many more have been proposed. Several of these strategies aim to augment CAR-T function by arming CAR-T cells with additional molecules or combining them with an additional therapy.

For example, boosting expression of some cytokines could make it easier for CAR-T cells to infiltrate solid tumors (9). Cytokines—small proteins secreted by certain immune cells—can enhance tumor-destroying activities of other immune cells, including T cells. “Armored” CAR-T cells, engineered with specific cytokine receptors or engineered to express stimulatory cytokines, have the potential to improve CAR-T therapy’s efficacy (10).

Other proposed strategies for enhancing CAR-T function include engineering CAR-T cells to be insensitive to immunosuppressive conditions and combining CAR-T therapy with immune checkpoint inhibitors (2). However, many of these approaches raise the risk of cytokine release syndrome, a toxic and potentially lethal side effect of CAR-T therapy resulting from excessive inflammatory cytokines in the circulatory system.

One combination therapy approach that has already demonstrated promise in early clinical trials is a messenger RNA (mRNA) vaccine that enhances the proliferation of CAR-T cells. The mRNA vaccine leads to target antigen expression on T-cell-activating immune cells (i.e., antigen-presenting cells). The resulting cell proliferation helps the therapy persist in the immunosuppressive solid-tumor environment and allows the therapy to be administered at lower initial doses. The clinical trial investigating CLDN6-directed CAR-T therapy, mentioned previously, used this strategy in a subset of patients (6). In the preliminary study, 43% of patients treated with a combination mRNA vaccine and CAR-T therapy experienced tumor shrinkage. Still, the efficacy and safety of this method need to be tested and validated in additional trials—approximately 40% of patients treated in the CLDN6 study developed manageable cytokine release syndrome.

Many of the challenges facing CAR-T therapy for solid tumors remain unresolved. However, if history is a guide, these obstacles are not insurmountable. Blood cancers are often selected for development of novel therapies because tumor cells circulating in the blood are easier to access than tumor cells in tissue, and treatments are easier to deliver. Treatment options, such as chemotherapy and stem-cell transplant, were first developed for blood-based cancers and then were modified to treat solid tumors. A number of recent advancements—including the identification of solid-tumor-specific antigens, the development of armored CAR-T cells, and mRNA combination therapies—are bringing this targeted immunotherapy for solid tumors closer to reality.

1. Mullard, A. FDA approves first CAR T therapy. 

 (10), 669–669. DOI:10.1038/nrd.2017.196
2. Marofi, F.; Achmad, H.; Bokov, D.; et al. Hurdles to Breakthrough in CAR T Cell Therapy of Solid Tumors. 

 (1),140. DOI:10.1186/s13287-022-02819-x
3. Chen, N.; Li, X.; Chintala, N. K.; Tano, Z. E.; Adusumilli, P. S. Driving CARs on the Uneven Road of Antigen Heterogeneity in Solid Tumors. 

, 103–110. DOI:10.1016/j.coi.2018.03.002
4. Kailayangiri, S.; Altvater, B.; Wiebel, M.; Jamitzky, S.; Rossig, C. Overcoming Heterogeneity of Antigen Expression for Effective CAR T Cell Targeting of Cancers. 

 (5), 1075. DOI:10.3390/cancers12051075
5. Du, H.; Yang, X.; Fan, J.; Du, X. Claudin 6: Therapeutic Prospects for Tumours, and Mechanisms of Expression and Regulation. 

 (3), 677. DOI:10.3892/mmr.2021.12316
6. Mackensen, A. BNT211-01: A Phase I Trial to Evaluate Safety and Efficacy of CLDN6 CAR T Cells and CLDN6-Encoding mRNA Vaccine-Mediated In-Vivo Expansion in Patients with CLDN6-Positive Advanced Solid Tumours. Presentation at the 2022 ESMO Congress, Paris, France, Sept. 9–13, 2022.
7. Society for Neuro-Oncology, Session 3: Immunotherapy: Hype and Hope. Presentation at the First Annual Conference on CNS Clinical Trials, 

, Oct. 1–2, 2021.
8. Mustang Bio, Mustang Bio Announces Initial Phase 1 Data on MB-105 for Patients with PSCA-positive Castration Resistant Prostate Cancer. Press Release, Oct. 26, 2020.
9. Mollica Poeta, V.; Massara, M.; Capucetti, A.; Bonecchi, R. Chemokines and Chemokine Receptors: New Targets for Cancer Immunotherapy. 

. DOI: 10.3389/fimmu.2019.00379
10. Hawkins, E. R.; D’Souza, R. R.; Klampatsa, A. Armored CAR T-Cells: The Next Chapter in T-Cell Cancer Immunotherapy. 

Brian Huber is vice-president of Therapeutic Areas, Drug Development, and Consulting, and Tamie Joeckel is global business lead of the Cell and Gene Therapy Group; both at ICON.

Articles

Features

There are various challenges associated with the development of CAR-T therapies for solid tumor cancers.


Difficulties in Expanding CAR-T Cell Therapy into Solid Tumors

Continuous manufacturing has the potential to offer benefits in terms of reduced costs, footprint, raw material consumption, and byproduct and emission generation combined with increased process consistency and product quality. Regulatory submission timelines can also be advanced by more than 12 months and approval times by three months compared to products generated via batch manufacturing (1). Not surprisingly, the US Food and Drug Administration (FDA) encourages the development of continuous processes, and these processes are slowly becoming more prevalent in both small-molecule and biologics manufacturing. It is expected, in fact, that in the near future continuous operations will be the norm rather than the exception, according to Hibreniguss Terefe, director of research and development at Catalent. As such, outsourcing providers that develop continuous manufacturing expertise and leverage this technology can establish a differentiating competitive advantage.

Hot-melt extrusion (HME) by its nature is a continuous process, and its integration with other continuous manufacturing operations has the potential as an amorphous solid dispersion (ASD) solution to offer more benefits than just enhanced solubility and bioavailability for poorly soluble APIs. “Given that HME is one of the best tools for enhancing solubility, linking HME processes effectively with other unit operations such as tableting/capsule filling will reduce the number of unit operations, ease scale-up to commercial production, and ultimately help patients realize earlier access to products with positive economic impacts for sponsors as well,” states Purushottam Singnurkar, vice-president and head of formulation development at Syngene International Limited.

Formulating drug substances into ASDs is a widely accepted approach to enhancing the solubility and bioavailability of poorly soluble molecules, according to Terefe. “The conversion of a crystalline API into an amorphous form by dispersing and immobilizing it in a polymeric carrier can be achieved through solvent- or fusion-based technologies. Spray drying is a solvent-based process, while HME is fusion-based technology,” he observes.

In addition to improved solubility, other benefits of using HME are good process control, scalability, and avoidance of solvents, notes Hannes Fuderer, technical operations manager with AbbVie Contract Manufacturing. “Good process control enables balancing of incoming variability into the extrusion process and reduces the variability of the extrudate itself to improve the performance of downstream processing. Good scalability provides the opportunity for faster development and transfer from
lab through pilot to commercial scale and affords flexibility to accommodate volume and extruder-scale changes during life-cycle management,” he explains.

“The ability to practically transfer material inputs continuously and have them transformed into output materials that are continuously removed leads to increased product quality assurance and enhanced product capability and control,” adds Singnurkar. He also comments that the fact that HME is a “green technology” that involves fewer processing steps than spray drying and freeze drying provides further advantages.

HME takes place in a twin-screw extruder, which is, according to Terefe, a continuous, versatile, and highly efficient self-wiping small mass mixer amenable to process analytical technology (PAT). That is why process parameters can be well controlled and HME processes can be readily scaled from R&D to commercial-scale equipment. “Once process parameters are established at a given equipment scale, the batch size is then a function of time and can be easily changed by running the process for a longer or shorter period without needing to change other process parameters,” he notes.

In addition, HME offers a high degree in flexibility and many use cases. “Based on the HME process design, there are many options to integrate an HME process into a fully continuous process or combine it with discontinuous up- and/or downstream processes if required, such as batch blending to feed the extruder or storage of extrudate intermediate prior to further (batch-wise) processing into final drug product,” Fuderer says. HME can also be used for potent compounds and due to the equipment design it typically results in high yields.

An HME unit operation is usually performed as a continuous process through a sequentially assembled equipment system consisting of powder feeder(s), optional liquid pump(s), a twin-screw extruder, a conveyor, and a pelletizer (or a chill roll flaker) working in a harmonized and continuous manner, Terefe notes. The extrudate, however, is typically handled as an intermediate and further processed as a batch, limiting HME to a semi-continuous process.

On the upstream side, the material feed can be a mixed powder blend or individual streams of different ingredients (API and excipients) fed directly. Either approach can be performed continuously, according
to Fuderer.He also notes that, based on material properties or to increase the throughput, the blend can be densified prior to extrusion by a continuous roller compactor or side-stuffer.

The extrudate, meanwhile, can be shaped into nearly any form by the design of the extruder die in combination with several cutting and shaping technologies that are also all continuous processes, Fuderer says. Common shapes are flakes, pellets, and beads depending on the downstream unit operation. “It is possible rather than collecting and buffering the shaped and cooled extrudate in containers prior to further processing, it can be dosed immediately to the next unit operation as the mass flow is still controlled,” he adds.

Integrating the extrusion process with other upstream and downstream semi-continuous unit operations such as continuous blending, milling, tablet pressing (direct compression), and tablet coating would, Terefe says, create a fully end-to-end continuous solid-oral-dosage-form manufacturing process. “Combining a continuous HME process with continuous downstream operations could be envisioned as a viable means for taking full advantage of a continuous process to manufacture solubility- and bioavailability-enhanced products,” he concludes.

One example provided by Singnurkar involves transfer of the hot extrudate directly to dies of suitable sizes for the manufacture of 3D tablets. “Integration eliminates many process steps such as cooling and milling of the extrudate and mixing with excipients, among others,” he says. Any integration of continuous operations without a centralized computer system for control and the implementation of PAT tools for constant process monitoring will, however, reduce the likelihood of success, Singnurkar stresses.

Understanding the critical material attributes (CMAs) of the API and polymer, such as the melting and glass-transition temperatures is also important for developing high-performing HME processes. “The machine settings, including the screw configuration, screw diameter-to-length-ratio, barrel-free volume, distribution of heating and cooling zones, die-orifice size and shape, and the cooling system are equality important. Critical process parameters include the barrel temperature, screw speed, residence time, and throughput,” Singnurkar from Syngene observes.

Controlling material inputs often presents the greatest challenge for HME process optimization, according to both Fuderer and Terefe. “Blend homogeneity, dosing accuracy, and risk of blend segregation during powder conveying are important issues that must be managed,” Fuderer stresses.

Inconsistent and inaccurate feeding of input material into the twin-screw extruder may be caused by poor flow properties of certain raw materials, or very low amounts of certain excipients such as plasticizers and surfactants, Terefe notes. “Feeding all of the components separately at an appropriate ratio of feed rates, as reflected in the formulation composition, would be ideal for a well-harmonized continuous
process, but this assumes that no additional pre-extrusion unit operations are necessary,” he says. Poorly flowing APIs may need to be preblended with a carrier polymer, and often, with additional flow-enhancing excipients, Terefe adds.

Fuderer does point out, though, that one advantage of the HME process is that variances in blend homogeneity and dosing are smoothened to a certain extent, and therefore, variances will not immediately impact extrudate quality.

Blend segregation, however, must be avoided during powder conveying into the extruder, according to Fuderer. This issue is particularly associated with discontinuous batch blending, as it poses higher risk for segregation at bin changes or if the upstream equipment runs empty.

In cases where the poor flow properties of the API or any excipient cannot be overcome by simple blending, Terefe observes that a pre-extrusion granulation step may be required. “Appropriate selection of the powder feeders with suitable feeder screw designs and the choice of liquid pumps for accurate liquid feeding without pulsation can help alleviate many of the input material feeding challenges,” he comments. Introducing a continuous blending process upstream of the extrusion step can also be beneficial for formulations for which simple blending cannot overcome these challenges, Terefe says.

Optimum HME processes generate extrudate with acceptable critical quality attributes (CQAs), such as amorphicity, content uniformity, and purity. Many CQAs impact downstream unit operations, according to Terefe, and thus it is crucial to have online monitoring capabilities (such as near-infrared spectroscopy for evaluating an extrudate’s crystallinity and content uniformity) to track these properties. Fortunately, says Fuderer, if HME processes are properly developed, they are robust and have good process control, and thus typically exhibit only minor variances in physical properties of extrudate intermediate that could impact downstream processing due to HME process performance.

Improper identification of critical material attributes and CQAs for HME processes can, believes Singnurkar, impact the uniformity, degradation profile, and dissolution behaviour of the final drug products. Misidentification of CPPs, meanwhile, can impact the milling of extrudates which can affect compressibility and thus make tabletting difficult. In addition, the API loading and miscibility of the API with the polymeric carrier can also, he says, significantly impact downstream processing.

It is the physical properties of the extrudate that are most important for downstream processing, Fuderer agrees. He adds, however, that they are mainly dependent on the product composition and less dependent on the HME process parameters such as the temperature profile. “As long as the product composition is controlled (e.g., blend homogeneity or ratio of solid and liquid feeds), no impact is expected on downstream processing,” he states.

In addition to product composition, Terefe emphasizes the importance of achieving consistent and controlled material throughput that is harmonized with downstream processes. For example, he points out that the material feed rate into a mill impacts particle size distribution, which may lead to inconsistency in the dissolution of the final product. Inconsistent material input into the continuous direct blending process downstream may also lead to poor blend uniformity, resulting in poor content uniformity of the final tablets.

Here again, the HME process benefits from good monitoring and control technologies. “Twin screw extruders typically have features for controlling and monitoring material throughput consistency, allowing the feed rate, extrusion load, and melt pressure to be continuously measured and monitored in real time,” Terefe explains. Any fluctuation in one of these parameters is a direct indication of material throughput inconsistency and the need to adjust the process.

Ultimately, the successful use of HME to enhance solubility and bioavailability of poorly soluble APIs manufactured in a fully continuous process, as is the case of any continuous manufacturing process, requires a well-engineered process design that can be controlled, Terefe contends. “When developing an HME process, there is a broad choice in polymers, equipment design, and development and scale-up approaches. It is important to involve appropriate subject matter experts at each stage to ensure the highest quality and most robust process for commercial manufacturing,” adds Fuderer.

The polymer and composition as well as the equipment and screw design are typically defined in early development at small extruder scale, according to Fuderer. At this stage, it is very important to understand how the material behaves in the extruder to prevent any issues to product quality or processability during scale-up because the opportunities to make changes to the composition later on are limited, he observes.

The processibility of the input material must be considered, says Terefe. For example, he highlights the need to understand the flow properties of the excipients in order to select appropriate feeders and determine pre-extrusion blending requirements.

“Investigating all possible variables that can impact product quality at the early stage can be challenging, however,” Fuderer comments. “Defining a design space that ensures product quality and processability, but also gives enough flexibility for post-development changes performed during lifecycle management (process and cost improvements, yield increases, supplier notifications for raw materials, etc.) is essential,” he concludes.

A well-planned process design that considers all technical and commercial perspectives and the company’s long-term strategy is fundamental, Terefe agrees. “The type of product(s) to be manufactured, the process flow, and unit operations need to be well understood, and the core equipment, along with necessary accessories, process control for each unit operation, and the CQAs of intermediate output material must be identified,” he states.

An effective means for achieving these goals is to use a quality-by-design (QbD) approach, according to Terefe. “A thorough risk assessment of CMAs and CPPs that impact CQAs for each unit operation must be conducted, along with identifying mitigation and control strategies,” he explains.

In addition, because continuous manufacturing aims to facilitate real-time batch release, a good understanding of each unit operation, both independently, and in combination with all other unit operations working in tandem, is essential, according to Terefe. In addition to PAT and real-time process analytics, he notes that model-based process optimization using relevant output data from sensors and processes is important.

It is also highly recommended, notes Fuderer, to keep process requirements for continuous processing in mind when developing HME processes to ensure that not only the HME process is developed to its optimum, but also that the interfaces to the up- and downstream unit operations guarantee final drug product meeting the desired quality.

Furthermore, well-organized and planned process integration into a computerized system that complies with GMP and good automated manufacturing process requirements needs to be established, as do proper IT structures and supervisory and control systems, Tenefe says. Such a centralized computer system that is integrated with various unit operations and PAT tools and provides real-time quality and process control is, in fact, essential for achieving consistent and optimum continuous HME processes, contends Singnurkar.

1. Mahesh R. An FDA Self-Audit of Continuous Manufacturing for Drug Products. FDA Podcast, 

. 28 June 2022. (Accessed March 30, 2023).

Cynthia A. Challener, PhD, is a contributing editor to 

When one is using continuous hot-melt extrusion to enhance solubility, process control is essential.

Addressing Poorly Soluble APIs with Continuous Hot-Melt Extrusion

Waters Corporation and Sartorius announced a new analytics collaboration on June 5, 2023. This agreement, which expands on their existing agreement that focused on upstream bioprocessing analytics, aims to develop integrated analytical solutions for downstream biomanufacturing.

According to a company press release, the collaboration will use Waters’ liquid chromatography and Sartorius’ multi-column chromatography platforms to develop a more comprehensive analytical data solution. This system will be used for downstream batch and continuous manufacturing with the goal of improving yields, reducing waste, and cutting costs.

“From the beginning of our collaboration with Sartorius, we’ve strived to give bioprocess engineers faster and more direct access to critical quality attribute information about their drug products in the name of improving production yields and getting drugs to patients faster,” said Jon Pratt, senior vice-president, Waters Division, in the release. “Based on the positive response of customers to our collaborative efforts with upstream bioprocessing analytics, we see tremendous benefit to combining [our platforms] to bring timely point-of-decision analytics to downstream biomanufacturing for monoclonal antibodies, recombinant proteins, vaccines and AAV gene therapies.”

“Now that intensified, continuous manufacturing of biologics is becoming a reality, there is a greater need for real-time analytical measurement,” said René Fáber, head of Bioprocess Solutions Division, Sartorius, in the release. “The value of combining technologies from Sartorius and Waters lies in bringing fundamentally important analytics to the point where it is needed and giving bioprocess engineers a more complete understanding of their downstream manufacturing processing and its effects on drug product quality. We believe this can have significant impacts on drug production costs by helping to increase yields and reduce waste.”

News

Sartorius and Waters will collaborate to develop integrated analytical solutions for downstream biomanufacturing.

Sartorius and Waters Expand Analytics Collaboration

Domino Data Lab, a data science and artificial intelligence (AI) platform company, announced various new capabilities at the Rev 4 conference on June 1, 2023. The expansions to the company's MLOps platform for developing and deploying custom large-language models and generative AI applications are designed to enable democratized access to various AI ecosystem changes. Expansions include a new AI project hub, additional cloud-based offerings, and the Model Sentry capability suite.

The new AI project hub uses pre-trained foundation models and project templates to connect users and enable them to select an optimal foundation model as well as to connect users to their data and generate code to fine-tune that data. The hub also has various auto-scaling compute clusters for large-scale distributed data preparation and model training.

The company’s new cloud offerings include Domino Cloud for Life Sciences (DCLS), an audit-ready specialized AI cloud platform intended for use in the pharmaceutical industry. DCLS is designed to accelerate drug discovery, optimize research workflows, and maintain strict regulatory compliance within a secure, collaborative, and fully managed platform.

The Model Sentry is a suite designed to mitigate model risks, implement responsible AI practice, and eliminate AI development overspend. The solution uses a unified model registry for complete lineage tracking, as well as automated model cards for auditing purposes.

"AI is an existential business imperative. The winners will be those who wield it with speed, responsibility, and fiscal savvy," said Nick Elprin, CEO and co-founder of Domino Data Lab, in a company press release. "We're backing our customers with the resources to outshine in these key areas and unleash AI to change the trajectory of civilization."

New Technology

Domino Data Lab's expanded platform includes a new project hub, additional cloud offerings, and the Model Sentry solution suite.

Domino Data Lab Expands AI Platform

On June 1, 2023, Lonza announced that it acquired Synaffix, a Netherlands-based biotechnology company with an antibody drug conjugate (ADC) technology platform. Under the deal, Lonza will initially pay €100 million (US$107 million) in cash and up to €60 million (US$64 million) in additional performance-based consideration. While it is now a Lonza company, Synaffix will continue to operate under the Synaffix name and will further expand its operations in Oss, The Netherlands, to prepare for further innovation and growth.

Synaffix’s ADC technology platform includes payload and site-specific linker technologies that will enhance and extend Lonza’s integrated ADC services, including Lonza’s early-phase offering. The ADC technology platform comprises proprietary GlycoConnect, HydraSpace, and toxSYN technologies, which can significantly enhance the efficacy and tolerability of ADCs, according to a company press release.

Through the acquisition, Lonza will combine its development and manufacturing capabilities with Synaffix’s ADC technology platform, which the companies expect will provide a comprehensive service to rapidly discover, develop, scale up, and commercialize novel and differentiated ADCs. The combination is also expected to streamline the path from discovery to clinic and commercialization.

“The acquisition of Synaffix underlines the strategic position of bioconjugates within Lonza’s portfolio, expands our offering in this fast-growing market and enhances our value proposition for clinical customers. With Synaffix, our combined … knowledge and capabilities have the capacity to support both clinical and commercial needs,” said Ulrich Osswald, vice-president, Licensing, Lonza, in the press release.

“On our mission to bring Synaffix’s ADC technologies to patients, we are excited to become part of Lonza, and, thus, through strong and immediate synergies, ensure a robust technology and manufacturing platform for our licensees as they progress into the late-stage clinical and commercial development phase. We can now also leverage the potential offered by Lonza to fast-track technology innovations in bioconjugates beyond cytotoxic ADCs,” said Peter van de Sande, CEO, Synaffix, in the release.

Lonza will gain access to R&D capabilities, including payload and site-specific linker technology, through its acquisition of ADC company, Synaffix.

Lonza Acquires Synaffix in ADC Deal

Revvity, Inc. announced on May 18, 2023, a new license agreement with AstraZeneca for the technology underlying technology in its Pin-point base editing system, which is a next-generation modular gene editing platform with a strong safety profile.

The Pin-point system and the base editing technology is defined as allowing highly efficient, precise single and multi-gene editing without unintended impact on cell viability or functionality. According to the press release, this newer editing system uses a modified Cas enzyme that only marks one strand of the DNA, which allows for a more controlled approach to gene distribution and base correction.

Different from other editing systems, the pin-point system is completely modular, allowing for different components to be selected for optimal performance specific to the gene targets. Additionally, Revvity has also developed a novel proprietary method to leverage the base editing mechanism to insert genes, like creating an allogeneic CAR-T cell therapy by knocking in a CAR while knocking out immune markers at the same time, according to the press release.

“Our fundamental goal for the Pin-point platform is to translate the technology from pre-clinical research into the clinic, and ultimately, impact patient lives,” said Alan Fletcher, PhD, senior vice president, Life Sciences at Revvity, in a press release. “In that vein, we are delighted to announce this non-exclusive agreement with AstraZeneca to support their creation of cell therapies for the treatment of cancer and immune-mediated diseases.”

The pin-point system is completely modular, allowing for different components to be selected for optimal performance specific to the gene targets.

New License Agreement Announced for Next-Generation Base Editing Technology 

ProBioGen, a Berlin-based company specializing in the development and manufacture of APIs, announced its new lentivirus packaging cell line on May 17, 2023. Lenti.RiGHT is a lentivirus production platform based on human embryonic kidney 293 packaging cells.

According to a company press release, the new line is capable of producing lentiviral particles with titers between 107 and 108 transducing units per mL. It includes stable integration of gag-pol, rev, and vesicular stomatitis virus-G proteins.

"With our Lenti.RiGHT platform we have developed a new standard for efficient large-scale lentivirus production and CAR–T [chimeric antigen receptor T cell] manufacturing,” said Volker Sandig, chief scientific officer, ProBioGen, in the release. “It enables an inducible, scalable, and efficient production of high-titer lentiviral particles for gene transfer applications.”

ProBioGen’s Lenti.RiGHT is a lentivirus production platform for use in gene transfer applications.

ProBioGen Launches Lentivirus Packaging Cell Line

Gilead Sciences and Arcus Biosciences, a US-based clinical-stage biopharmaceutical company, announced on May 15, 2023 that they are expanding a previously announced research collaboration to now include development of therapies for treating inflammatory diseases. Their initial collaboration agreement, worth potentially more than $1.6 billion, focused on oncology (1).

Under the expanded collaboration, Arcus will receive an upfront payment of $35 million. Arcus will initiate research programs against up to four targets that are jointly selected by both parties and that are applicable to inflammatory diseases. Gilead would have the option to license each program at two separate, prespecified time points. If Gilead exercises its option for the first two target programs at the earlier time point, then Arcus would be eligible to receive up to $420 million in option and milestone payments as well as tiered royalties for each optioned program. For any other option exercised by Gilead for the four target programs, the two parties would have rights to co-develop the candidates. In addition, both parties would share global development costs and co-commercialize and share profits in the United States for optioned programs.

“We are pleased to build upon Gilead’s efforts in inflammation with the expansion of our strategic collaboration with Arcus,” said Flavius Martin, executive vice-president, Research, Gilead Sciences, in a company press release. “Arcus is an excellent partner with clear strengths in discovery and development, and we believe this partnership will significantly accelerate our progress in developing transformative new therapies for inflammatory diseases.”

“Since its founding, Arcus has been creating and developing therapeutic interventions that can modulate the immune system to treat cancer. Through this expansion of our partnership with Gilead, we can combine our research expertise in immunology and small-molecule drug discovery with Gilead’s strong clinical experience in inflammation,” said Terry Rosen, CEO, Arcus, in the release. “The research collaboration facilitates much earlier alignment between Gilead and Arcus on our discovery and development activities, while enabling Arcus to expand into inflammation in a capital-efficient manner.”

1. Gilead Sciences, Gilead Sciences and Arcus Biosciences Establish 10-year Partnership to Co-develop and Co-commercialize Next-generation Cancer Immunotherapies. Press Release, May 27, 2020.

Gilead Sciences and Arcus Biosciences have expanded their research collaboration to include inflammatory diseases in addition to oncology. 

Gilead Sciences and Arcus Biosciences Expand Research Partnership

Murlsa Bio’s tissue-specific Extracellular Vesicle (EV) isolation technology, NEXPLOR, will be presented at the International Society for Extracellular Vesicles (ISEV) annual meeting, which is intended to be a new route for biomarker discovery in liquid biopsy and precision medicine.

The new method was developed to isolate tissue-specific EVs from the blood in addition to using a workflow to analyze their diverse multi-omics content. The ISEV annual meeting will continue to showcase NEXPLOR and how it has been used to discover novel liver cancer biomarkers for the surveillance of individuals at high risk.

“NEXPLOR can isolate specific sub-populations of EVs, such as liver-specific EVs, from complex fluids like blood. This is an important step forward to develop EV-based liquid biopsy and precision medicine applications,” said Tomás Dias, PhD, CTO at Mursla Bio, in a press release.

NEXPLOR is engineered to improve the translation of EV-based diagnostics into clinics. Further, this complements its ultrasensitive validation technology, NEXOS, which was created to offer a high throughput and clinically compatible 

 diagnostics test from the newly discovered panel of tissue-EV biomarkers, according to the press release.

“Imagine you could examine any bodily tissue, at any time, without resorting to invasive procedures. This would completely transform how we manage cancer and chronic disease. The liquid biopsy field has been built on that principle,” said Pierre Arsène, founder and CEO of Mursla Bio, in a press release. “Unfortunately, existing approaches based on circulating free DNA have been restrictive, providing only a limited snapshot of cellular activity. This is because they are not tissue-specific and overlook the complexity of biological processes. We believe our method marks a substantial progression and have initiated a clinical study to deliver our first liquid biopsy test, which we expect to complete by early 2024. We aim to launch in the US in 2025.”

The new method was developed to isolate tissue-specific EVs from the blood in addition to using a workflow to analyze their diverse multi-omics content. 

Mursla Bio Discovers New Biomarker Approach in Precision Medicine

TriLink Biotechnologies launched its new cap analog, CleanCap M6, on May 9, 2023, which is expected to help developers and researchers maximize the impact of their messenger RNA (mRNA) therapeutics and vaccines while reducing overall manufacturing costs, according to a company press release. The introduction of CleanCap M6 technology is intended to improve mRNA potency with the highest protein expression of any CleanCap analog to date.

“TriLink’s portfolio of CleanCap mRNA capping technology is expected to be the new go-to capping method in the very near future—it is the future,” said Kate Broderick PhD, chief innovation officer at Maravai LifeSciences, in a press release. “What excites me most about this novel analog is its ability to make mRNA an even more powerful therapeutic than we have seen previously.”

The first CleanCap analog was launched in 2017, and since then, the capping technology has been incorporated in one of the first commercially approved COVID-19 vaccines.

“mRNA is clearly an emerging therapeutic modality where mRNA vaccines and therapeutics are expanding rapidly,” said Drew Burch, EVP of TriLink’s Nucleic Acid Products division, in a press release. “CleanCap M6, and the entire CleanCap portfolio, joins a strong roster of synthesized nucleic acids, NTPs, and more that we expect to continue to grow.”

TriLink Biotechnologies Introduces CleanCap M6 Analog

Through quantitative structure-activity relationship (QSAR) models, predictions can be made for a drug substance itself, intermediates, prioritizing experimental inquiries into the potential effects of newly identified drugs of abuse, and more. FDA’s Division of Applied Regulatory Science’s (DARS) computational toxicology and pharmacology research has been focused on the development of highly curated data sets and QSAR models for endpoints of regulatory interest.

Two statistical-based QSAR models were developed by DARS to predict drug permeability across the blood brain barrier (BBB) with the purpose to assist regulators with abuse liability assessment of drug metabolites or other materials related to drug substances. According to FDA, these models are useful in predicting whether an unknown substance of abuse can permeate the BBB to produce effects predicted by the Public Health Assessment via Structural Evaluation (PHASE) approach. The agency defines PHASE as a multi-component computational approach that determines if newly emerging drug substances on the street-drug market are at a risk to public safety, according to a press release.

Researchers from DARS developed reliable QSAR models by harvesting data for approximately 1000 molecules from multiple publicly available data sources. Further, the models were trained exclusively on results from 

 experiments in rodents where the ratio of drug in the brain to that in blood or plasma was determined. Then, two different commercial software packages were used to construct the models, and classification thresholds were chosen for both models based on the tradeoff between the specificity and sensitivity of their predictions.

The models and databases developed through the DARS are used internally by the agency to inform and support regulatory decisions for drug products, and they are available to the public through commercial QSAR software vendors with whom FDA’s Center of Drug Evaluation and Research has formal Research Collaboration Agreements, according to the press release.

FDA’s Division of Applied Regulatory Science’s (DARS) computational toxicology and pharmacology research has been focused on the development of highly curated data sets and QSAR models for endpoints of regulatory interest.

BioPharm International's BP Elements, June 2023