Behind the Headlines Episode 27

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Small Molecules, APIs, and Excipients—Trends, Challenges, and Opportunities

Drug Digest September 2025

Artificial intelligence, machine learning, and novel instruments are helping drug developers.

Enhancing Bioanalysis and Drug Development with Advanced Tools and Technologies

J.P. Morgan Report Lists Biologics, Obesity, China

Top Trends Reshaping Pharma R&D

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On March 6, 2024, the European Medicines Agency (EMA) announced that the Data Analysis and Real World Interrogation Network, DARWIN EU, has plans to expand capacity for real-world data (RWD) studies in 2024 by adding 10 new data partners. The network currently includes 20 public or private institutions from 13 European countries with access to data from approximately 130 million patients in Europe.

was initiated in 2022 between EMA and the European Medicines Regulatory Network as a coordination center to provide evidence on the use, safety, and effectiveness of medicines in a timely and reliable manner. Data regarding diseases, populations, and performance of medicines are collected from real-world healthcare databases across the European Union. Data obtained by DARWIN EU are converted into a common data model, and the data are kept local and analyzed locally by data partners.

These data are used by EMA and national competent authorities in the EU to make regulatory decisions. DARWIN EU supports EU regulators by establishing a catalogue of observational data sources, by providing validated real-word data, and by carrying out non-interventional studies. The project became fully operational in 2024, which includes involvement from both data partners and regulators as well as the ability to conduct studies and provide answers to EMA scientific committees and national competent authorities. The next goal is for DARWN EU to leverage the data obtained and increase geographical coverage and scope.

The project gathers data from partners in The Netherlands, Belgium, United Kingdom, France, Portugal, Spain, Norway, Finland, Estonia, Denmark, German, Hungary, and Croatia. The initiative projects adding approximately 20 additional partners by the end of 2025. Protocols and results of all DARWIN EU studies are publicly available in the 

In the two years since the project was started, 14 RWD studies have been completed and 11 are ongoing. Topics of studies include drug utilization, vaccine effectiveness, disease epidemiology, and patient characterization. Recent completed studies include (1):

A study examined treatment patters in adults and children with systemic lupus erythematosus (SLE). Results were provided to EMA’s Pediatric Committee for the potential use in clinical trials and to see the similarities between adults and children.

Another study looked at more than 30,000 patients diagnosed with multiple myeloma between 2012 and 2022 in Europe. The study was the first of two pilots to gather data on patient characteristics, treatment patters, and chances of survival for these patients.

A utilization study was conducted to understand the use pattern of endothelin receptor antagonists and phosphodiesterase-5 inhibitors in pulmonary arterial hypertension.

An investigation on the annual incidence and prevalence of the use of opioids in seven countries was conducted to determine duration of prescription opioid use, characterization of users, and prescribing and dispensing indications. A study on the use of Take-Home Naloxone to treat opioid overdose was also conducted.

A cohort study to estimate background rates of serious adverse events and causes of death in severe asthma was conducted.

Study results for these and other studies will be shared with relevant EMA committees and stakeholders. Results will be scaled up with onboarding of data from new partners added in 2024 and 2025. The project aims to conduct 70 RWD studies in 2024 and other 140 studies per year from 2025 onward.

Big Data Steering Group (BDSG): 2023 Report.

Articles

EMA plans to add 10 partners to its real-world data initiative, DARWIN EU, in 2024.

Europe's DARWIN EU Data Program Adds Capacity

Feliza Mirasol is the science editor for 

On March 7, 2024, Johnson & Johnson (J&J) announced the completion of its acquisition of Ambrx Biopharma, a clinical-stage biopharmaceutical company, in a deal valued at approximately $2 billion. Ambrx specializes in a proprietary synthetic biology technology platform to design and develop next-generation antibody drug conjugates (ADCs).

The acquisition provides J&J the opportunity to design, develop, and commercialize targeted oncology therapeutics using Ambrx’s proprietary ADC technology, which incorporates highly specific-targeting monoclonal antibodies (mAbs) securely linked to a potent chemotherapeutic payload. The goal of the platform is to achieve targeted and efficient elimination of cancer cells without the prevalent side effects that are typically associated with chemotherapy, according to a company press release.

“We’re pleased to welcome Ambrx’s talented scientific team and proprietary ADC platform to Johnson & Johnson. We look forward to continuing the development of ARX517, which represents a potential first- and best-in-class PSMA [prostate-specific membrane antigen]-targeting ADC for the treatment of metastatic castration-resistant prostate cancer,” said Yusri Elsayed, global therapeutic area head, Oncology, Johnson & Johnson Innovative Medicine, in the press release. “This significant opportunity sets the stage for advancing next-generation ADCs with the aim of delivering differentiated solid tumor therapies that improve patients’ lives.”

“The Ambrx team has developed a promising pipeline and ADC platform that will be a strong complement and strategic fit to our oncology innovation strategy,” said Biljana Naumovic, worldwide vice-president, Oncology, Johnson & Johnson Innovative Medicine, in the release. “ADCs are transforming the solid tumor treatment paradigm by leveraging antibody–antigen interactions to release cytotoxic payload directly to tumor cells. This acquisition underscores our ambition to deliver enhanced, precision biologics to transform the treatment of cancers, including prostate cancer.”

In earlier news, the company announced on March 6, 2024 (1) that it has submitted a Type II variation application to the European Medicines Agency seeking approval for an indication extension of DARZALEX (daratumumab) subcutaneous (SC) formulation. Specifically, the application is seeking approval of the mAb in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) to treat adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant (ASCT).

This submission is supported by data from a Phase III study (PERSEUS) evaluating D-VRd induction and consolidation therapy, ASCT, and daratumumab with lenalidomide (D-R) maintenance therapy in comparison to VRd, ASCT, and R maintenance. Results demonstrated that the study met its primary endpoint of progression-free survival.

“The impressive results from the PERSEUS study highlight the potential of this daratumumab subcutaneous-based regimen to transform patient outcomes and provide an effective therapy option in newly diagnosed, transplant-eligible multiple myeloma,” said Craig Tendler, vice-president, Clinical Development, Diagnostics, and Global Medical Affairs, Johnson & Johnson Innovative Medicine, in a company press release. “We are committed to advancing innovative regimens, such as D-VRd, as we strive towards the elimination of this complex disease. We now look forward to working with the EMA on the review of this submission.”

1. Johnson & Johnson. Johnson & Johnson Submits Application to the European Medicines Agency for DARZALEX (daratumumab)-based Quadruplet Therapy for the Treatment of Patients with Transplant-Eligible, Newly Diagnosed Multiple Myeloma. Press Release. March 6, 2024.

Johnson & Johnson’s $2 billion acquisition of Ambrx boosts its pipeline of next-generation ADCs for cancer treatment.

J&J Completes $2 Billion Ambrx Acquisition, Boosts Pipeline for Next-Gen ADCs

On March 7, 2024, FDA published two final guidance documents regarding analytical procedures in order to facilitate regulatory evaluations and flexibility in postapproval change management of analytical procedures. The documents were developed in collaboration with the International Council for Harmonisation (ICH). Q2(R2)

outlines principles of analytical procedure validation, including the analytical use of spectroscopic data. 

harmonizes scientific approaches for analytical procedure development and provides principals for risk-based postapproval change management.

The Q2(R2) document is directed to common uses of analytical procedures and applies to analytical procedures used for release and stability testing of commercial drug substances and products. It includes information on validation studies, validation during the life cycle of an analytical procedure, reportable ranges, stability-indicating procedures, and multivariate analytical procedures. Specifically, it covers specificity/selectivity, ranges, accuracy and precision, and robustness. The document has two annexes: one provides a selection of validation tests; the other provides illustrative examples of analytical techniques.

“This guidance presents elements for consideration during the validation of analytical procedures included as part of registration applications. Analytical procedure validation forms a part of the analytical procedure life cycle, as described within [ICH] guidance for industry Q14 

 (March 2024) (ICH Q14). This ICH guidance for industry, Q2(R2) 

 (ICH Q2), provides guidance on selection and evaluation of the various validation tests for analytical procedures. This guidance includes a collection of terms and their definitions, which are meant to bridge the differences that often exist between various compendia and documents of the ICH member regulatory authorities. The objective of validation of an analytical procedure is to demonstrate that the analytical procedure is fit for the intended purpose. Further general guidance is provided on validation studies for analytical procedures,” the guidance states. “Approaches other than those set forth in this guidance may be applicable and acceptable with appropriate science-based justification. The applicant is responsible for designing the validation studies and protocol most suitable for their product,” it further stresses.

The Q14 document discusses minimal versus enhanced approaches to analytical procedure development. Specifically, it addresses analytical target profiles, risk management, parameter ranges, procedure control strategies, multivariate analytical procedures, and real-time release testing. It also provides guidance on submission of analytical procedure information. The documents Annex gives examples of application of ICH Q14 principals and an example of multivariate model life cycle components.

“Using the tools described in the ICH guidance for industry Q12 

Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management

 (May 2021) (ICH Q12), the guidance describes principles to support change management of analytical procedures based on risk management, comprehensive understanding of the analytical procedure, and adherence to predefined criteria for performance characteristics. Knowledge gained from application of an enhanced approach to analytical procedure development can provide better assurance of the performance of the procedure, can serve as a basis for the analytical procedure control strategy and can provide an opportunity for more efficient regulatory approaches to related postapproval changes,” the guidance states.

The two final guidance documents replace draft guidance documents published in August 2022.

FDA has published final guidance documents regarding validation and development of analytical procedures.

Final Analytical Procedures Guidance Published

Felicity Thomas is the former Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

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Global pharmaceutical company, AstraZeneca, has revealed its latest investment plans, which involve spending a total of £650 million ($828 million) within the United Kingdom. This influx of money is expected to boost the country’s life science sector and grow the economy.

In a press release, issued by the UK Government on March 6, 2024, it was announced that AstraZeneca’s investment will be used across Liverpool and Cambridge in the UK. The company’s manufacturing site in Speke, Liverpool will receive £450 million ($573 million), which will be used for the research, development, and manufacture of vaccines. Additionally, AstraZeneca will use the remaining £200 million ($255 million) to expand its presence in Cambridge with a facility that will be built adjacent to its R&D Discovery Centre (DISC), which is already located on the life sciences cluster site.

“We are sticking to our plan to make the UK one of the best places in [the] world to invest in developing and manufacturing new, innovative medicines—both protecting public health and growing our economy,” said Jeremy Hunt, the UK’s Chancellor of the Exchequer, in the press release. “AstraZeneca’s investment plans are a vote of confidence in the attractiveness of UK as a Life Sciences superpower and strengthen our resilience for future health emergencies.”

“AstraZeneca’s planned investment would enhance the UK’s pandemic preparedness and demonstrates our ongoing confidence in UK life sciences,” added Pascal Soriot, CEO of AstraZeneca in the press release. “We will continue to support the UK in driving innovation and patient access, building on the strong foundations which have been put in place.”

Furthermore, adding to the boost that the investment will afford the UK to improve resilience to potential future pandemics and health threats, AstraZeneca and the UK Health Security Agency (UKHSA) are planning to partner on advancing science for the development and evaluation of vaccines. This partnership will take advantage of the technology at AstraZeneca’s Speke site in Liverpool and also the UKHSA’s Vaccine Development Evaluation Centre at the Porton Down site in Salisbury, UK.

“This investment will bolster the development of the UK’s vaccine capabilities and life sciences sector—critical components of the country’s resilience to future health threats,” explained Dr. Isabel Oliver, chief scientific officer at UKHSA, in the press release. “UKHSA majors on researching and developing new ways to strengthen the country’s defences against all health hazards—including future pandemics—and works routinely with a range of commercial and academic partners. We are looking forward to working with AstraZeneca to collectively protect the population’s health.”

“The UK is a global leader in the research and development of life saving vaccines. Today’s announcement is testament to this country’s Life Science capabilities—and our continued commitment to pandemic preparedness and global health,” stated Victoria Atkins, Secretary of State for Health and Social Care of the United Kingdom, in the press release. “As well as creating new highly skilled jobs, this investment will help maintain the UK’s position at the forefront of tackling emerging diseases, and support our work to make our healthcare system faster, simpler, and fairer.”

New plans laid out by AstraZeneca will see £650 million ($828 million) be invested into the UK.

AstraZeneca Set to Boost the UK’s Life Sciences Sector with Investment Plans

Opportunities in sterile fill/finish available based on new capacities by Simtra BioPharma Solutions

Simtra BioPharma Solutions Announces Expansion Project and Unique Opportunities

Role of Simtra BioPharma Solutions in the sterile fill/finish arena

New capacities available through Simtra based on global expansion

Sterile fill/finish opportunities to deliver better care to patients

Videos

Sean Knight, Simtra BioPharma Solutions, reacts to the company's global expansion efforts and investment in sterile fill/finish.

Simtra BioPharma Solutions Reacts to Expansion and Unique Opportunities in the Industry

Chris Spivey is director of Industry Relations and Strategic Partnership, MJH Life Sciences.

Fabian Gerlinghaus, co-founder and CEO, Cellares

There’s no doubt that things are moving quickly in the field of cell and gene therapy. Less than a decade into market availability, there are more than 10 FDA-approved cell therapies available (1), including first-in-class tisagenlecleucel (Kymriah; Novartis), which was approved in 2017 for the treatment of acute lymphoblastic leukemia in children and young adults. Soon after, three more CD19-specific CAR T-cell therapies were approved by the FDA for the treatment of different B-cell malignancies, namely axicabtagene ciloleucel (Yescarta), brexucabtagene autoleucel (Tecartus), and lisocabtagene maraleucel (Breyanzi), and more continue to come to market for 

An August 2023 report from market research firm Roots Analysis (2) revealed that “over 1,000 cell and gene therapy candidates are currently being investigated for the treatment of various disease indications.” The report went on to say that “in order to ensure the optimum use of their resources and augment their revenue generation opportunities, a number of cell therapy companies engaged in this market offer contract services, in addition to their in-house manufacturing capabilities. In recent years, several big pharma players have undertaken initiatives, including establishing strategic partnerships, seeking investment from venture firms, and carrying out expansion projects, in order to enhance their capabilities.”

Small Footprint Automated Closed Production Platforms for CAR-T and Other Advanced Therapies

One of those companies leading the charge is San Francisco-based Cellares, a self-titled Integrated Development and Manufacturing Organization (IDMO) that provides cost savings, scalability, and drug product quality improvements versus traditional manufacturing techniques. In an interview with 

, Fabian Gerlinghaus, CEO and co-founder, Cellares, set the stage to understand what it took to innovate in a fiercely complex technology and tightly regulated space.

In the first segment of this interview, Gerlinghaus describes the scalability achieved with the Cell Shuttle platform and integrated consumable cartridge automated platform. All unit operations take place inside the single-use consumable cartridge. Cellares can load up to 16 cartridges into the Cell Shuttle, running up to 16 different processes simultaneously. According to Gerlinghaus, the Cell Shuttle reduces the amount of labor required by about 90% due to the automation, saying “it’s equivalent to about 100 different bench top instruments in one machine, in a very compact, tight space [requiring] about 90% less facility space. So, you put those two things together, a 90% reduction in labor required.” He goes on to emphasize that this results in about a 50% lower price per batch compared with conventional CDMOs. In a complex set of manufacturing operations, full automation can apparently “reduce process failure rates by about 75% compared with open and manual cell type manufacturing methods based on bench-top equipment” by greatly reducing both contamination and operator error.

Watch part 1 of our interview with Gerlinghaus below:

Fabian Gerlinghaus of Cellares discusses the company's innovative cell and gene therapy platform.

Fabian Gerlinghaus on Cellares' Platform Innovation

(1). Approved Cellular and Gene Therapy Products. US Food and Drug Administration. Updated February 21, 2024. Accessed March 6, 2024. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products
(2). Top 10 Cell and Gene Therapy Companies. Roots Analysis. August 2023. https://www.rootsanalysis.com/key-insights/10-leading-cell-and-gene-therapy-companies.html

Cellares CEO Fabian Gerlinghaus shares how an automated, closed-production platform with a small footprint can dramatically impact cost savings and scalability for cell and gene therapies.

Cellares Innovates With Automated Cell and Gene Therapy Platform

AbbVie and OSE Immunotherapeutics, a clinical-stage immunotherapy company, announced on Feb. 28, 2024 that they have entered into a strategic partnership to develop OSE-230, a monoclonal antibody (mAb) in development to treat chronic and severe inflammation. The mAb is currently in pre-clinical development.

Under the agreement, OSE Immunotherapeutics will receive a $48 million upfront payment and is eligible to receive up to an additional $665 million in clinical development, regulatory, and commercial milestones. OSE Immunotherapeutics will also be eligible to receive potential tiered royalties on global net sales of OSE-230. AbbVie will have an exclusive global license to develop, manufacture, and commercialize OSE-230.

OSE-230 is designed to activate ChemR23, a G-protein coupled receptor (GPCR) target, which may offer a new mechanism by which chronic inflammation can be resolved. Activating ChemR23 may modulate the functions of both macrophages and neutrophils, according to a company press release.

"This collaboration underscores our commitment to expanding our immunology portfolio with the ultimate goal of improving the standard of care for patients living with inflammatory diseases globally," said Jonathon Sedgwick, senior vice-president and global head of discovery research, AbbVie, in the press release. "By leveraging our expertise in immunology drug development, we look forward to advancing OSE-230, which offers a novel mechanism-of-action to treat chronic inflammation."

"We are very pleased to collaborate with AbbVie … to drive our OSE-230 program forward," said Nicolas Poirier, chief executive officer, OSE Immunotherapeutics, in the release. "This partnership represents a major milestone in our company's progress and recognizes the value of our innovative R&D capabilities. I would like to thank all our employees who helped us reach this milestone through dedication and hard work."

OSE Immunotherapeutics' pipeline also includes the following candidates:

Tedopi (immunotherapy-activating tumor-specific T-cells, off-the-shelf, neoepitope-based).

 This candidate is a cancer vaccine and is the company's most advanced product. It has generated positive results in a Phase III trial (Atalante 1) in patients with non-small cell lung cancer who are experiencing secondary resistance after checkpoint inhibitor failure. Tedopi is also in other ongoing Phase II trials, sponsored by clinical oncology groups, in combination treatment scenarios for solid tumors.

OSE-279 (anti-programmed cell death protein 1 [PD-1]).

 This candidate has generated its first set of positive results in an ongoing Phase I/II study in solid tumors. OSE-279 is the primary therapy derived from the company’s bispecific fusion protein platform, BiCKI.

OSE-127 - lusvertikimab (humanized mAb antagonist of interleukin 7 [IL-7] receptor).

 This candidate is in an ongoing Phase II study in ulcerative colitis and in ongoing preclinical research in leukemia.

 This mAb was developed in partnership with Veloxis Pharmaceuticals, an Asahi Kasei company, for use in transplantation treatment. It is in ongoing Phase I/II studies in renal transplant and an ongoing Phase I study in the United States.

BI 765063 and BI 770371 (anti-signal-regulating protein alpha [SIRPα] mAb on CD47/SIRPα pathway).

 These candidates were developed in partnership with Boehringer Ingelheim for treatment of advanced solid tumors. They have demonstrated positive Phase I dose-escalation results in monotherapy and in combination, particularly with the anti-PD-1 antibody, ezabenlimab. They are also in an ongoing international Phase Ib clinical trial in combination with ezabenlimab alone or with other drugs for treating patients with recurrent/metastatic head and neck squamous cell carcinoma and hepatocellular carcinoma.

In addition to these pipeline candidates, OSE Immunotherapeutics also expects to generate further potential candidates based on its three proprietary drug discovery platforms:

Pro-resolutive mAb platform, which focuses on targeting and advancing the resolution of inflammatory conditions and optimizing the therapeutic potential of targeting neutrophils and macrophages in immunology and inflammation (I&I). OSE-230 is the first candidate generated by this platform. Additional discovery programs are ongoing on new pro-resolutive G protein-coupled receptors.

Myeloid Checkpoint platform, which aims to optimize the therapeutic potential of myeloid cells in immuno-oncology (IO) by targeting immune regulatory receptors that are expressed by macrophages and dendritic cells. BI 765063 and BI 770371 are the most advanced candidates generated by this platform. There are also additional ongoing discovery programs, with positive preclinical results obtained in monotherapy studies with new anti-C-type lectin-like receptor-1 mAbs.

Cytokine platform, which focuses on leveraging the Cis-delivery of cytokine in IO and I&I. BiCKI is a bispecific fusion protein platform. It is built on the key backbone component of anti-PD-1 combined with a new immunotherapy target. This combination aims to increase anti-tumor efficacy. BiCKI-IL-7v is the most advanced candidate generate by the BiCKI platform, which targets anti-PD-1xIL-7. There are ongoing additional discovery programs on Cis-demasking technologies.

Under a global license and collaboration agreement, AbbVie and OSE Immunotherapeutics will aim to develop OSE-230, a mAb for treating chronic inflammation.

AbbVie Partners with OSE Immunotherapeutics on Novel mAb for Chronic Inflammation

CordenPharma announced on March 6, 2024 that it is expanding capacity at its Frankfurt, Germany site to accommodate the manufacture of early clinical-phase peptide APIs for its pharmaceutical and biotech customers. The company is planning for the expansion to be operational in the second quarter of 2024 with authorization by German authorities completed in the second half of 2024.

As part of the expansion, 1000 square meters of manufacturing space will be added to the Frankfurt site. The site will add two fully equipped lines comprised of a solid phase peptide synthesizer, high-pressure liquid chromatography, liquid phase isolation equipment, and quality control laboratories. The quality control labs will feature in-process control, starting material batch release, and good manufacturing practice (GMP) stabilities. The GMP manufacturing area will produce peptide APIs from gram to kilogram range for clinical Phase I and Phase II requirements with later transfer to the company’s late-phase and commercial manufacturing Boulder, Colo., site in the United States.

The GMP expansion will support the launch of the integrated services between the company’s CordenPharma Frankfurt site and CordenPharma Caponago, which offers services for injectable drug products. The integrated peptide-injectable services will be tailored to the individual customer and will deliver technical, manufacturing, and regulatory support for investigational new drug (IND)/investigational medicinal product dossier (IMPD) filings and first-in-human (FIH) clinical trials. Customers will benefit from working with one contract development manufacturing organization with a single contract, quality agreement, and project management. The offering also features API route selection, salt and solubility studies, API characterization, and reference standard qualification. Formulation development, analytical method development, and validation will also be provided. Assistance with technical writing for IND/IMPD submissions will also be available.

"With our new early clinical GMP peptide manufacturing investment in Frankfurt and the launch of seamlessly integrated peptide API to injectable drug product services, CordenPharma is uniquely positioned to deliver customized CMC [chemistry, manufacturing, and controls] support for biotech customers and facilitate their successful IND/IMPD submissions and start of FIH clinical trials. We believe the offer will bring added-value and increased efficiency to our customers, and ultimately enhance the well-being of their patients,” said Stéphane Varray, CordenPharma’s Global Peptide Platform director, in a press release.

previously expanded the Frankfurt site in 2020

 to include an increase in available lab space by 25% and the addition of a dedicated explosion proof area.

the company invested €9.7 million (US$10.9 million) i

nto the design and installment of a new clinical trial development facility for manufacturing oral solid dosage drug products at its Plankstadt facility near Heidelberg, Germany.

 the company also launched its new Lipid NanoParticle (LNP) Starter Kits 

for the formulation of messenger RNA (mRNA)-based therapeutics, such as mRNA vaccines or gene therapies. The starter kits are designed to provide researchers and developers with the essential components needed to create and optimize their own LNPs for mRNA delivery. The kits allow users to fine-tune the LNP formulation process and achieve production of nanoparticles with the desired physicochemical characteristics, such as polydispersity index ≤0.2 and a size range between 30–150 nm, depending on specific LNP reaction conditions, lipid composition, and cargo used.

The company is expanding GMP capacities at its Frankfurt site to manufacture early clinical-phase peptide APIs.

CordenPharma Expands Clinical Peptide Capacity

How Adare Pharma Solutions is evolving to keep pace with changes in the industry.

Adare Pharma Solutions - Evolving to Meet the Future Needs of Customers

Oral solid dose capabilities and small molecule expertise

Recent and planned expansions in packaging, high potency, and controlled substances offerings as well as a new nitrosamine mitigation offering

Wide-scale resources have increasingly been deployed to find, characterize, validate, bank, and file patents for cancer neoantigens. It has been a biological landgrab echoing the single nucleotide polymorphism (SNP) fervor at the turn of the century. In a conversation late in 2023 with Maravai’s chief innovation officer Kate Broderick and Accuitas’ CEO Tom Madden on future applications for messenger RNA (mRNA)-based therapeutics, the notion came up as a potential lynch pin. Broderick commented that, “there was a beautiful study that came out of a large group in the UK [United Kingdom] called the TRACERx Study where they actually monitored people's cancers over time and fairly frequently, and within a matter of a month, some of these tumors had completely changed their neoantigen profile. So, to [Madden]'s point, the need to have really unprecedented speed to make this, the promise of personalized vaccines prominent … is absolutely key now” (1). However, lacking in mature and effective tools and equipment, activities have been labor intensive and, for the most part, produced only halting successes.

. from the La Jolla Institute for Immunology with a new platform approach described in a February American Association for the Advancement of Sciences (AAAS) paper (2). This new approach appears to work well on cancers pictured as evading patients’ immune systems, in part because these cancers do not carry many mutations. However, while these cancers are not infiltrated by cancer-fighting immune cells, the tumors do appear to trigger some cancer-fighting T cells and can perhaps be entrapped, thus “heating up” cold cancers.

The first principles that follow might seem complex, but some amount of future therapeutic target tractability may well require basic understanding of those principles. From the paper’s introduction “the genetic instability underlying neoplastic transformation can also provide tumor-specific targets for host T cells. These include function-altering mutations in so-called ‘driver’ genes, which endow the tumor with growth and survival advantages, as well as tumor-specific variants of ‘passenger’ genes that lack an obvious protumorigenic function” (2).So far so good; cancers behave and interact differently from regular tissue in ways that leave characteristic biological trails that can be tracked. Along this trail researchers recognize mutated peptides bound to the surface of human leukocyte antigen (HLA) molecules for recognition as neoantigens by patients’ CD8 and CD4+ T lymphocytes. Researchers have been aware of neoantigens for some time and have wanted to target these tumor specific targets; however, it has been a substantial challenge to do so.

A typical traditional neoantigen discovery setup relies on next-generation sequencing (NGS), complex algorithms/databases, and a certain distrust regarding the utility of the eventually upturned somatic nonsynonymous mutations (NSMs). The process is expensive and slow. A second method assesses T cells in peripheral blood or tumor-infiltrating lymphocytes (TILs). This can be “technically challenging or require specialized cellular reagents, such as autologous dendritic cells, thus limiting their utility in routine neoantigen screening using nominal clinical samples” (1). The La Jolla team set out instead to forge an “unbiased and HLA-independent strategy for the functional validation of spontaneous neoantigen-specific CD4+ and CD8+ T cell responses that uses NGS-guided selection to nominate NSMs for functional recognition testing in a short-term culture of autologous peripheral blood mononuclear cells (PBMCs), which reports on both T helper cell 1 (TH1) and TH2 cytokines. Using this approach (herein referred to as ‘IPV’ for identify-prioritize-

validate), we now show that preexisting CD4+ and CD8+ T cell responses can be identified and the T cell receptors (TCRs) that mediate them can be isolated at rates that are about 10-fold higher than class I HLA binding–based predictive approaches across a spectrum of tumor types and degrees of tumor mutational burden using routinely available clinical samples” (2). It will likely have been understood that by integrating elements of both traditional approaches, this new platform performs in a more HLA-agnostic and clinic-capable manner and is, henceforth, a healthy step ahead in terms of reliably churning out tumor target information—especially regarding low mutation tumor profiles. It is also a step toward a better understanding of tumor microenvironment interactions with an individual’s immune system, which alone makes it an effort worth celebrating.

There are some drawbacks and limitations, however, and these can be found in the discussion section of the AAAS paper. But the expectation to “routinely and reliably identify natural tumor-specific neoantigens and the TCRs that recognize them” will indeed “be crucial to the development of precisely and accurately targeted immunotherapies that can effectively offer therapeutic benefit while avoiding off-tumor toxicities” (2), which is a long-sought goal in oncology research now visibly present as a functional platform technology.

, Oct. 17, 2023.
2. Miller, A.; Schoenberger, S.; Peters, B.; Cohen, E. A functional identification platform reveals frequent, spontaneous neoantigen-specific T cell responses in patients with cancer. 

 (736), eabj9905. DOI:10.1126/scitranslmed.abj9905

Accurately targeted immunotherapies through reliable neoantigen recognition enable personalized medicine development.

Featured Content

Behind the Headlines Episode 27

Ask the Expert

Drug Digest September 2025

Enhancing Bioanalysis and Drug Development with Advanced Tools and Technologies

Top Trends Reshaping Pharma R&D