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Researchers at UT Southwestern Medical Center have discovered that increasing the levels of a protein called BACH2 can make engineered anti-cancer immune cells behave more like stem cells, thereby boosting their therapeutic effectiveness. This study, published in Nature Immunology, proposes a new strategy for improving the efficacy of these immune cells, known as Chimeric Antigen Receptor (CAR) T cells."Using mouse models of solid cancer, we found that programming CAR-T cells to acquire stem-cell-like properties during the manufacturing process significantly enhances their anti-tumor activity. This fine-tuning of CAR-T cells may represent a powerful strategy to overcome key barriers in solid tumor immunotherapy," said Dr. Tuoqi Wu, who co-led the study with Dr. Chen Yao. How CAR-T Cells Work and Their ChallengesSince 2017, CAR-T cells have been approved by the U.S. Food and Drug Administration as a cancer therapy. These cells are created by collecting a patient's own T cells and then genetically engineering them to fight that patient's specific cancer.While CAR-T cells have shown great promise against blood cancers such as leukemia and lymphoma, they only provide durable remission in a portion of cases. Furthermore, CAR-T cells have remained largely ineffective against solid tumors.This inefficiency stems primarily from a phenomenon called exhaustion, Dr. Wu explained. Constant stimulation by antigens on the surface of cancer cells eventually leaves CAR-T cells unable to fight cancer, proliferate, or respond to immune checkpoint inhibitor drugs. They also exhibit signs of metabolic dysfunction and eventually die. Understanding why exhaustion occurs is key to making CAR-T cells a more effective therapy for all cancers.The Link Between Stem-Cell-Like Properties and the BACH2 ProteinA few years ago, Dr. Wu and Dr. Yao found an important clue while studying T-cell exhaustion in chronic viral infections. In that research, T cells showed varying tendencies to exhaust. However, the T cells least prone to exhaustion possessed more stem-cell-like properties. Those cells with higher "stemness" produced more of a protein called BACH2.Figure 1. LT stem-like CAR T cells develop after leukemia clearance and upregulate BACH2 expression. (Hu T, et al., 2026)To test whether this was also true for CAR-T cells, the researchers cultivated these cells from mice. Much like the previous study, cells with higher BACH2 gene expression maintained more stem-cell-like properties than those with lower expression.Cells with more BACH2 were also less prone to exhaustion and more resistant to leukemia than cells with less BACH2. The researchers found similar results when observing BACH2 expression in human CAR-T cell samples.Boosting BACH2 to Improve CAR-T TherapyBased on these findings, the researchers generated mouse CAR-T cells that produced varying levels of BACH2. The CAR-T cells with the highest BACH2 levels maintained the most stem-cell-like properties and were most resistant to exhaustion when grown in lab cultures.Cat.No.Product NamePriceCSC-DC001294Panoply? Human BACH2 Knockdown Stable Cell LineInquiryCSC-SC001294Panoply? Human BACH2 Over-expressing Stable Cell LineInquiryAD01684ZHuman BACH2 adenoviral particlesInquiryLV06017Lhuman BACH2 (NM_001170794) lentivirus particlesInquiryCDCB187124Rabbit BACH2 ORF clone (XM_008263219.1)InquiryCDCR032966Mouse Bach2 ORF clone (NM_001109661.1)InquiryCDFH001615Human BACH2 cDNA Clone(NM_001170794.1)InquiryCDFR003892Rat RGD1311072 cDNA Clone(NM_001033890.1)InquiryCDFR009796Rat RGD1562865 cDNA Clone(NM_001135754.1)InquiryIn another strategy, the researchers transiently increased the amount of BACH2 produced by CAR-T cells during the manufacturing process before injecting them into a mouse model of neuroblastoma—a solid malignancy that develops in nerve precursor cells. Compared to typical CAR-T cells, this adjustment significantly improved the cells' ability to control cancer and inhibited tumor growth.Dr. Wu and Dr. Yao stated that their study suggests increasing BACH2 production in CAR-T cells may provide a viable technology to help them resist exhaustion while fighting both blood tumors and solid tumors. They hope to eventually test this strategy in clinical trials.ReferenceHu T, et al. BACH2 dosage establishes the hierarchy of stemness and fine-tunes antitumor immunity in CAR T cells. Nature Immunology, 2026: 1-11.
The delivery of therapeutic genes is fundamental to gene therapy. Adeno-associated virus (AAV) has become the predominant vehicle for carrying gene payloads due to its superior flexibility in gene splitting and robust gene reconstruction efficiency. However, its limited packaging capacity remains a significant hurdle for the transduction of larger genes.Recently, researchers developed AAV with translocation linking (AAVLINK), a technology that utilizes Cre/lox-mediated intermolecular DNA recombination to achieve the in vivo reassembly of large genes. The related research findings were published in the journal Cell.Figure 1. AAVLINK drove expression of intact Shank3 or SCN1A and rescued behavior and seizure phenotypes of mutant mice, respectively. (Lin J, et al., 2026)Compared to conventional methods, AAVLINK allows for flexible gene-splitting designs, enables highly efficient full-length gene reconstruction, and significantly minimizes the production of aberrant truncated proteins.Utilizing animal models, researchers found that AAVLINK facilitates the robust expression of the full-length Shank3 gene and significantly rescues autism-like behavioral phenotypes in Shank3-deficient mice. Similarly, AAVLINK-mediated delivery of SCN1A, a large gene associated with epilepsy, restored gene expression and alleviated seizure phenotypes in mutant mice. These findings provide strong evidence that AAVLINK supports the functional delivery of large therapeutic genes within the nervous system.Furthermore, the researchers developed AAVLINK 2.0 by integrating a destabilized Cre recombinase. This design offers stricter temporal control over recombination activity, maintaining high gene reconstruction efficiency while reducing potential safety concerns.Cat.No.Product NamePriceAAV00020ZCre Adeno-associated virus(AAV Serotype 5)InquiryAAV00044ZCre Adeno-associated virus(AAV Serotype 1)InquiryAAV00045ZCre Adeno-associated virus(AAV Serotype 2)InquiryAAV00046ZCre Adeno-associated virus(AAV Serotype 6)InquiryAAV00047ZCre Adeno-associated virus(AAV Serotype 8)InquiryAAV00048ZCre Adeno-associated virus(AAV Serotype 9)InquiryAAV00061ZCre-GFP Adeno-associated virus(AAV Serotype 1)InquiryAAV00062ZCre-GFP Adeno-associated virus(AAV Serotype 2)InquiryAAV00063ZCre-GFP Adeno-associated virus(AAV Serotype 5)InquiryAAV00064ZCre-GFP Adeno-associated virus(AAV Serotype 6)InquiryAAV00065ZCre-GFP Adeno-associated virus(AAV Serotype 8)InquiryAAV00066ZCre-GFP Adeno-associated virus(AAV Serotype 9)InquiryAAV00100ZSynapsin-Cre-GFP AAV (Serotype 8)InquiryAAV00111ZAAV9-CMV-Cas9InquiryAAV00123ZscAAV1-CreInquiryUsing the AAVLINK strategy, the researchers constructed a vector library covering 193 large genes associated with genetic disorders, including autism and epilepsy, and validated the gene reconstruction capability of all constructs. The library also includes five CRISPR-based genetic tools, demonstrating the broad applicability of the AAVLINK platform.This study introduces a strategy capable of delivering large gene payloads via AAV, thereby offering therapeutic possibilities for diseases previously considered inaccessible to AAV-based gene therapy.ReferenceLin J, et al. AAVLINK: A potent DNA-recombination method for large cargo delivery in gene therapy. Cell, 2026.
Monoclonal antibodies (mAbs) are a class of critical biomolecules highly valued in diagnostics, research, and therapeutics. Extensive efforts are dedicated to improving the safety and efficacy of antibody therapies through an in-depth understanding of disease mechanisms, precision target screening, and the development of innovative antibody-related products for clinical use.Regulatory standards for the quality of antibody-related products depend heavily on a comprehensive mastery of their structural complexity, functional characteristics, production processes, and control measures. Critical Quality Attributes (CQAs) of mAbs include intrinsic (product-related) properties and extrinsic (process-related) factors.The primary reason for the efficacy of therapeutic monoclonal antibodies lies in their selectivity and the technological advancements driving their development. However, because a single molecule contains multiple functional domains, mAbs are complex proteins both structurally and functionally. This complexity impacts their regulation, production, and quality control. Regulatory scrutiny should carefully consider whether a mAb is fit for its intended use, while taking into account the antibody’s affinity for specific targets, its half-life, and its mechanism of action.Selection and Use of mAb Production Cell SubstratesTo produce bioactive mAbs with the necessary quality and consistency, stable cell lines must be used. If the cell substrate is genetically engineered, the expression system should be characterized in accordance with relevant ICH and WHO guidelines. Before using cell fusion or transformation techniques to immortalize B cells for mAb production, their safety must be carefully evaluated. When using human B lymphocytes as parental cell lines, careful consideration must be given to the possibility of contamination by defective prions or other pathogenic adventitious agents.Post-Processing of Monoclonal Antibody ProductionFollowing the growth and production phases, the recovery of mAbs from the cell substrate requires a procedure capable of consistently producing antibodies that meet their intended use. The specific details of downstream processes and their controls will vary for each product and manufacturer. Viral safety standards must also be met during downstream processing, which should include appropriate viral clearance purification processes based on the production system.Systematic Product Development to Ensure Quality ConsistencyQuality by Design (QbD) represents a systematic approach to product development. To guarantee consistent product quality, safety, and efficacy, this approach requires a deep understanding of the product, the manufacturing process, and the relevant control measures.Good Manufacturing Practice (GMP)GMP standards are developed to reduce trade barriers for pharmaceuticals, facilitate consistency in licensing approvals, and uphold rigorous quality assurance standards throughout the entire process of drug R&D, production, and regulation. The marketing authorization framework ensures that all medical products are evaluated by authorized agencies to verify compliance with safety, quality, and efficacy standards.Sterile Production Processes for Biological ProductsMonoclonal antibodies and vaccines require sterile production procedures to ensure consistent product quality amidst the inherent variability of biological materials.Manufacturing Processes for Biological ProductsVarious technologies, such as microbial and eukaryotic cell culture, biological tissue extraction, recombinant DNA methods, and hybridoma technology, are utilized to obtain biological products, including monoclonal antibodies.Regulatory Guidelines for Contamination PreventionThe European Union and the WHO have issued directives to mitigate the risk of microbial contamination during the manufacturing process, emphasizing compliance with air classification standards such as ISO 14644-1.Importance of Environmental Monitoring in Sterile ProductionRegular environmental monitoring, bioburden assessment, media fills, and container closure integrity testing are critical for maintaining sterility during the production process and must be regularly repeated and updated.Key Steps in Sterile Production ProcessesEssential stages such as final sterilizing filtration, aseptic filling, and vial capping require controlled environments with precise laminar flow conditions and adherence to specific room grades.Bioburden Testing ProceduresBioburden testing is conducted prior to final sterilization, using techniques such as membrane filtration, the pour plate method, and the spread plate method to estimate the number of aerobic microorganisms.Process Simulation Validation via Media Fill TestsMedia fill tests, which simulate sterile production procedures, are successfully completed three consecutive times to ensure process accuracy.HVAC System ConsiderationsHVAC systems play a pivotal role in preventing contamination and cross-contamination; therefore, they require careful consideration during the initial plant design and continuous monitoring of operating parameters.Importance of Filter Integrity Testing in HVAC SystemsHEPA filters in HVAC systems must undergo regular integrity testing, with the frequency of testing varying according to regulatory recommendations.Microbial Environmental Monitoring for Vaccine DistributionRigorous microbial environmental monitoring is essential to minimize microbial risks during the vaccine distribution process, emphasizing cleanrooms and environmental controls, including airborne particulate monitoring.Partner with Creative Biogene for Reliable Biosafety TestingAt Creative Biogene, we take pride in offering comprehensive, reliable, and compliant biosafety testing services that ensure the safety of your biological products. With our expertise, cutting-edge technology, and deep understanding of global regulatory requirements, you can rest assured that your products meet the highest safety standards.ReferenceNikita, A. Rai, A. Verma, et al., The Basics of Large-Scale Commercial Production of Monoclonal Antibodies. Industrial Microbiology and Biotechnology, 2025.
Recently, researchers from Oregon Health and Science University and Washington University in St. Louis published a research paper titled "Intracranial injection of genetically modified, mosquito non-transmissible Zika virus: Safety in primates and ramifications for brain tumor therapy" in the Cell sub-journal, Cell Reports Medicine.Glioblastoma (GBM) is an aggressive brain tumor with a median survival period of less than 21 months. Immune checkpoint inhibitors, peptide vaccines, and dendritic cell vaccines have not shown significant benefits in clinical trials. Over the past two decades, the standard of care for glioblastoma has remained largely unchanged, including surgery, radiation therapy, chemotherapy, and more recently, anti-mitotic Tumor Treating Fields.Glioblastoma typically recurs within 6 months even after maximum treatment, posing a significant clinical challenge. A highly heterogeneous subpopulation of glioblastoma stem cells (GSCs) is resistant to standard therapies and may be the underlying driver of recurrence. Furthermore, its tumor microenvironment (TME) is strongly immunosuppressive and lacks anti-tumor immune cells. Therefore, new therapeutic strategies are needed to address these challenges.Oncolytic viruses can infect and destroy tumor cells, offering a potential treatment for glioblastoma. A range of viruses, including H-1 parvovirus, reovirus, measles virus, Newcastle disease virus, vaccinia virus, poliovirus, adenovirus, herpes simplex virus, retrovirus, myxoma virus, and vesicular stomatitis virus, have been or are being studied as oncolytic virus therapies for GBM. However, these viruses do not exclusively infect glioblastoma stem cells, and to date, no virus has been successfully developed for widespread clinical application.Zika virus (ZIKV)-based oncolytic therapy is unique in that it specifically targets glioblastoma stem cells, shrinking tumor volume and extending survival in various mouse models of glioma.Although Zika virus causes congenital brain abnormalities in fetuses of infected mothers, it rarely infects the brains of adults. The research team demonstrated that ZIKV does not infect adult brain tissue samples from epilepsy surgeries but specifically infects SOX2+ glioblastoma stem cells from human glioblastoma slices. Additionally, in mice, intratumoral oncolytic Zika virus treatment enhanced the effects of systemic antibody-mediated PD-1 blockade.Glioblastoma is an incurable brain tumor. ZIKV has the ability to specifically kill glioblastoma stem cells, which are responsible for treatment resistance. In mouse models of glioblastoma, Zika virus also triggers an anti-tumor inflammatory response and prolongs survival.To support the clinical development of oncolytic Zika virus therapy and address safety concerns regarding intratumoral treatment, the research team modified the 3'untranslated region (3'UTR) of the Zika virus genome by deleting 10 nucleotides—Δ10 3'-UTR ZIKV. This elimination removes the possibility of the virus countering the innate antiviral immune response, and the modified virus cannot be transmitted by mosquitoes.Figure 1. Viral RNA and infectious virus levels in rhesus macaque brains 14 days after intracranial injection of Δ10 3'-UTR ZIKV. (Hirsch A J, et al., 2025).To further evaluate its safety, the research team injected Δ10 3'-UTR ZIKV into the brains of tumor-free rhesus macaques. Following injection, these primates showed no signs of clinical disease. Histologically, as expected, the Zika virus infection triggered mild inflammation that subsided within two weeks. After 14 days, no infectious virus was detected in the brain or any other organs. These findings support the safety of using Δ10 3'-UTR ZIKV in the brain and, combined with previous data, advance its clinical translation as an oncolytic and immunomodulatory therapy for glioblastoma.Cat.No.Product NamePriceCDCV050801ZIKV ancC ORF CloneInquiryCDCV050802ZIKV C ORF CloneInquiryCDCV050803ZIKV preM ORF CloneInquiryCDCV050804ZIKV pr ORF CloneInquiryCDCV050805ZIKV M ORF CloneInquiryCDCV050806ZIKV E ORF CloneInquiryCDCV050807ZIKV NS1 ORF CloneInquiryCDCV050808ZIKV NS2A ORF CloneInquiryCDCV050809ZIKV NS2B ORF CloneInquiryCDCV050810ZIKV NS3 ORF CloneInquiryCDCV050811ZIKV NS4A ORF CloneInquiryCDCV050812ZIKV 2K ORF CloneInquiryCDCV050813ZIKV NS4B ORF CloneInquiryCDCV050814ZIKV NS5 ORF CloneInquiryReferenceHirsch A J, et al. Intracranial injection of genetically modified, mosquito non-transmissible Zika virus: Safety in primates and ramifications for brain tumor therapy. Cell Reports Medicine, 2025, 6(12).
The site-specific insertion of gene-sized DNA fragments remains an unmet need in the field of genome editing. The IS110 family of serine recombinases was recently demonstrated to mediate programmable DNA recombination in bacteria using dual-specific RNA guides, known as bridge RNAs (bRNAs), which simultaneously recognize target and donor sites.Recently, Martin Jinek's team at the University of Zurich, Switzerland, published a research paper entitled "Programmable genome editing in human cells using RNA-guided bridge recombinases" online in Science. This study discovered programmable genome editing in human cells using RNA-guided bridge recombinases.In this study, researchers demonstrated that the bridge RNA-guided recombinase ISCro4, derived from Citrobacter rodentium, exhibits robust activity in human-derived cells. By engineering the bridge RNA to split into independent target-binding loops (TBL) and donor-binding loops (DBL) and applying precise RNA programming rules, they utilized ISCro4 to install kilobase-scale insertions at safe harbor loci, as well as perform programmable deletions and inversions at disease-related loci. Recombination rates for deletions and inversions in genome-integrated reporter constructs exceeded 10%. Furthermore, programmable genomic insertion of exogenous DNA was achieved with efficiencies surpassing 6%.CRISPR-Cas genome editing has revolutionized the treatment of genetic diseases. However, effective treatment for many multi-allelic genetic disorders requires correction strategies based on the site-specific insertion of large, gene-sized DNA payloads. This remains challenging to achieve using existing first- and second-generation CRISPR genome editors. Emerging technologies aiming to address this need include Prime Medicine-assisted site-specific integrase gene editing (PASSIGE), CRISPR-associated transposons (CASTs), engineered retrotransposons, and fusions of catalytically inactive Cas9 with transposases. However, these methods face several limitations, including large coding sizes that may hinder effective cellular delivery, off-target insertions, and the creation of genomic "scars". In this context, the recently discovered bridge RNA-guided recombinases, originating from the IS110 family of bacterial insertion sequence (IS) transposable elements, represent a promising class of programmable systems for genome engineering applications.IS110 bridge recombinases have been shown to catalyze site-specific recombination between target and donor DNA using bipartite RNA guides (referred to as bridge RNAs or seekRNAs). A bridge RNA contains two internal loops: a target-binding loop (TBL) and a donor-binding loop (DBL). Each loop contains two variable segments that base-pair with the top and bottom strands of the target and donor sites, respectively. Structural and biochemical studies of the IS621 recombinase have revealed that the recombination mechanism involves an initial nicking of the top strands of the target and donor, followed by strand exchange and ligation to create a Holliday junction intermediate, which is finally resolved through bottom-strand cleavage and ligation.Figure 1. Structural analysis of ISCro4 to enhance activity. (Pelea O, et al., 2026)In this work, the researchers show that the bridge recombinase ISCro4 is highly active in human cells and provide structural insights into its enhanced activity. Using either plasmid-based or all-RNA delivery, ISCro4 supports the programmable excision and inversion of several thousand base pairs and facilitates the insertion of donor DNA at genomic sites with efficiencies over 6%. Finally, the researchers evaluated the specificity and off-target activity of ISCro4. These results establish a framework for the development of bridge recombinases as next-generation editing tools that surpass current technological capabilities.Catalog No.Product NameInquiryCCPV-001pLX-U6-sgRNAInquiryCCPV-002pLX-sgRNA-zeoInquiryCCPV-003pGL3-U6-sgRNAInquiryCCPV-004pX459InquiryCCPV-005pCW-Cas9InquiryCCPV-006pHDE-35S-Cas9-mCherryInquiryCCPV-007p415-GaL-Cas9-CYC1tInquiryCCPV-008p426-SNR52p-gRNA.CAN1.Y-SUP4tInquiryCCPV-009pCMV-Flag-Cas9InquiryCCPV-010pCDNA-dCas9-VP64InquiryCCPV-011dCas9-VP64_GFPInquiryCCPV-012pHR-SFFV-dCas9-BFP-KRABInquiryCCPV-013pcDNA3.1-hLbCpf1-NLSInquiryCCPV-014pcDNA3.1-hAsCpf1InquiryReferencePelea O, et al. Programmable genome editing in human cells using RNA-guided bridge recombinases. Science, 2026: eadz1884.
Oncolytic viruses (OVs) represent a promising frontier in cancer therapy. These replication-competent viruses can infect both normal and tumor cells but selectively replicate within the latter, triggering an anti-tumor response. While the first FDA-approved OV therapy, Imlygic (based on HSV), has succeeded in treating melanoma via intratumoral injection, its efficacy remains limited against deep-seated or metastatic tumors.
The application and development of circRNA in the therapeutic field benefit from continuous innovation in in vitro synthesis technologies and the constant optimization of methodologies. Currently, the in vitro synthesis of circRNA is primarily categorized into two major types: chemical synthesis and enzymatic synthesis. Enzymatic synthesis can be further subdivided into protein ligase-mediated synthesis, self-splicing ribozyme synthesis, and hairpin ribozyme-mediated synthesis.
As research into the functions and mechanisms of circular RNA (circRNA) continues to deepen, the field has gradually expanded from basic scientific research to industrial applications, demonstrating significant potential particularly in drug development. In the process of drug R&D, circRNA is primarily categorized into two research directions: non-coding RNA and coding RNA.
The advent of immune checkpoint inhibitors, such as PD-1/PD-L1 antibodies, has been a revolution in oncology, providing hope for long-term survival to countless patients with advanced cancer. However, a harsh reality remains: only about 20% to 30% of patients benefit significantly, while more than half either show no initial response or develop resistance after a period of treatment. Overcoming this resistance to extend the benefits of immunotherapy to more patients is currently one of the most urgent challenges in oncology.
Chimeric antigen receptor (CAR) T-cell therapy has significantly transformed the treatment landscape for B-cell malignancies. However, its broader application remains hindered by complex manufacturing processes and the requirement for lymphodepletion chemotherapy, which limit patient accessibility.
