Designed to Combine.
Precigen advances the promise of precision immunology through novel multifunctional gene and cell therapies designed to work in combination to achieve efficacy and safety.
The UltraCAR-T® Advantage
- Non-viral multi-gene delivery
- Overnight manufacturing process
- Higher antigen-specific expansion and in vivo persistence
- Non-exhausted, stem-like T cell phenotype
- Ability to deplete with integrated kill switch
CAR-T cell therapies require new approaches for broader patient access
Chimeric antigen receptor T, or CAR-T, cell therapies have shown remarkable responses in patients with Hematologic B cell cancers; however, high cost and long delays due to complex and lengthy manufacturing processes are major obstacles to their broad adoption. Furthermore, autologous and allogeneic CAR-T cell therapies face challenges in the treatment of solid tumors due to their rapid exhaustion and limited persistence, which limits the duration of their anti-tumor response in the body.
UltraCAR-T: a new class of CAR-T cell therapy
The UltraCAR-T platform is fundamentally differentiated from the competition and has the potential to disrupt the CAR-T treatment landscape by increasing patient access through rapid manufacturing, lower manufacturing-related costs, and improved outcomes using advanced technologies for precise tumor targeting and control of the immune system.
Non-viral multigenic delivery system
UltraCAR-T cells utilize the non-viral Sleeping Beauty system, which has been optimized using our UltraVector® DNA construction platform to deliver a large multigenic payload at high efficiency. As a result, UltraCAR-T cells are precision-engineered to produce a homogeneous cell product that simultaneously expresses antigen-specific CAR, kill switch, and mbIL15 genes. Antigen binding, hinge and signaling domains of each CAR are optimized for tumor cell killing based on the target antigen expression profile. Every UltraCAR-T cell is equipped with our proprietary kill switch technology to enable their controlled elimination to improve the safety profile.
Precigen’s UltraCAR-T is the only platform to significantly reduce manufacturing and treating time for autologous CAR-T to just one day.
In vivo expansion and persistence
The key driver of improved UltraCAR-T performance is the expression of our proprietary membrane-bound interleukin-15, or mbIL15. IL-15 is a master regulator cytokine that promotes T-cell activation and expansion as well as survival of memory T cells to enhance anti-tumor response. mbIL15 is tethered to the cell surface and functions locally to enhance the functionality of the UltraCAR-T cell without systemic delivery of IL-15. Expression of mbIL15 is shown to enhance in vivo expansion in the presence of tumor antigens and prevent UltraCAR-T cell exhaustion leading to longer persistence and an enduring anti-tumor response that outlasts conventional CAR-T cells.
Conventional CAR-T cells struggle to contain growth of aggressive solid tumor cells (as expressed in green fluorescent protein) in a long-term in vitro culture consistent with their limited potential for persistence due to exhaustion. In stark contrast, UltraCAR-T cells exhibit sustained killing of tumor cells and inhibit tumor growth highlighting their potential for an enduring anti-tumor response.
Rapid, decentralized manufacturing process
UltraCAR-T cells are manufactured by a rapid, streamlined manufacturing process that forgoes the need for large, centralized facilities, lengthy manufacturing process resulting in exhaustion and limited in vivo life-span of current CAR-T cells and contributes to the high costs of therapies. Instead, UltraCAR-T manufacturing requires isolation of the patient’s own T cells after blood draw, followed by non-viral gene transfer using plasmid DNA at medical centers. The next day following the gene transfer, UltraCAR-T cells are infused into the patient. The UltraCAR-T manufacturing process can scale beyond the confines of a dedicated facility and provides a significant potential competitive advantage in the timeline and cost required to manufacture and deliver CAR-T therapies to patients.
We are currently evaluating three UltraCAR-T treatments in clinical trials. PRGN-3005 UltraCAR-T is an investigational therapy for advanced ovarian cancer; PRGN-3006 is an investigational therapy for relapsed or refractory AML and higher-risk MDS; and PRGN-3007, based on the next generation UltraCAR-T, is an investigational therapy targeting ROR+ hematological and solid tumors. We are now developing a library of UltraCAR-T to target various tumor antigens with the goal of providing personalized, autologous CAR-T treatment for cancer patients in a rapid and cost-conscious manner.
The AdenoVerse™ Immunotherapy Advantage
- Large payload capacity
- Low seroprevalance in humans
- Ability for repeat administration
- Durable antigen-specific immune response
- Highly productive manufacturing process
“Off-the-shelf” AdenoVerse Immunotherapy / Cytokine Therapy
The AdenoVerse Immunotherapy platform utilizes a library of proprietary adenovectors for the efficient gene delivery of vaccine antigens and cytokines to modulate the immune system. Our proprietary gorilla adenovectors are potent, have high payload capacity and are amenable to repeated patient administration. AdenoVerse therapies are manufactured using proprietary manufacturing cell lines and easily scalable production methodology. Superior performance characteristics and high yield manufacturing of AdenoVerse vectors combined with UltraVector technology allow us to engineer cutting-edge gene therapies to treat complex diseases.
Large genetic payload capacity
Our gorilla adenovectors can deliver up to 12kb of genetic payload in vivo, which is larger than other viral vectors currently ubiquitous in the gene therapy field. This allows us to engineer gene therapies that express multiple genes in a controlled manner.
Our gorilla adenovectors have very low seroprevalance in humans and thus are more suitable for repeated administration. Ability to redose patients is a major advantage of AdenoVerse immunotherapies since it can lead to boosted antibody and T cell responses and improved outcomes for patients.
AdenoVerse therapies are engineered to be replication deficient in vivo, and do not exhibit cytopathic or cytotoxic effects in normal human cells. Lack of in vivo replication and high yield manufacturing process reduces the regulatory and commercialization risks.
Durable antigen-specific immune response
Gorilla adenovectors engineered to present particular antigens have been shown to generate a high-level of durable antigen-specific neutralizing antibodies and effector T cell immune responses as well as an ability to boost these antibody and T cell responses via repeat administration in animal models.
We are developing multiple AdenoVerse gene therapies for immuno-oncology and infectious disease areas.
The ActoBiotics™ Advantage
- Food-grade bacteria with long history of safe use
- Local expression of genes at disease site
- Cost-effective and scalable manufacturing
- Convenient oral or topical delivery
ActoBiotics is a unique therapeutic platform precisely tailored for specific disease modification with the potential for superior efficacy and safety via oral or topical delivery of disease-modifying therapeutics directly to the relevant local mucosal sites. ActoBiotics work via genetically modified bacteria that deliver proteins and peptides to mucosal sites, enabling non-viral delivery of therapeutic agents.
Food-grade bacterium with easy genetic manipulation
ActoBiotics are generated by genetically modifying Lactococcus lactis (L. lactis), a well-characterized food-grade bacterium with a long history of safe use, to secrete multiple therapeutic agents, such as proteins, peptides, and antibodies, to enable simultaneous targeting of multiple pathways in one disease.
Cost-effective and scalable manufacturing
ActoBiotics are manufactured using an efficient, reliable cGMP process that is designed to easily scale for commercial supply. The ActoBiotics manufacturing process involves fermentation of genetically modified L. lactis, followed by concentration and freeze-drying and does not require costly purification processes, an advantage over conventional biologics.
Convenient, targeted delivery method with demonstrated safety
ActoBiotics can be delivered to the oral cavity through a mouthwash, intestinally via a capsule, or through other topical formulation. This delivery modality is designed to reduce the side-effects commonly attributed to systemic delivery and corresponding peaks in concentration. ActoBiotics product candidates have been well-tolerated in pre-clinical and clinical studies. Compared to conventional biologics, we believe ActoBiotics have potential to provide superior safety and efficacy via sustained release of appropriate quantities of select therapeutic agents.
- Therapeutic gene(s) inserted into L. lactis genome, removing an essential gene to ensure containment of the modified bacteria.
- Modified L. lactis incorporated into oral capsule, buccal rinse or topical solution for convenient delivery.
- After delivery, L. lactis secretes the inserted therapeutic agent(s) directly to the gut or buccal mucosa.
The Multifunctional Therapeutics Advantage
- Target multiple pathways simultaneously
- Preferential targeting at tumor sites
- Improved cytotoxic T cell activation
- Overcome TME suppression
Checkpoint inhibitors have had a significant impact on oncology treatment. However, a majority of patients fail to respond to PD1/PD-L1 inhibitors and among those that do, approximately one-third relapse.
Estimation of the Percentage of US Patients With Cancer Who Respond to Checkpoint Inhibitor Immunotherapy Drugs in 20181
Our multifunctional therapeutics platform is designed to address the unmet need of this patient population. Multifunctional therapeutics target checkpoint and immunosuppressive pathways in tumor microenvironment simultaneously to enhance activation and trafficking of T cells into tumor.
Treatment with PRGN-5001 promotes superior T cell infiltration into 3-D tumor spheroid compared to anti-PD1 and leads to improved anti-tumor effects in preclinical testing.
Checkpoint inhibitors, especially anti-PD1 treatments, have shown improved outcomes in a variety of advanced cancers, however, significant durable responses only occur in a minority of patients. A major factor for resistance to anti-PD1 treatment has been attributed to immunosuppressive tumor microenvironment and lack of adequate cytotoxic T cell infiltration into tumor. PRGN-5001 multifunctional therapeutic is engineered to simultaneously target checkpoint and immunosuppressive pathways to potentially improve the outcomes for patients who are resistant to checkpoint inhibitors.
Powerful gene programs to drive efficacy
UltraVector® platform incorporates advanced DNA construction technologies and computational models to design and assemble genetic components into complex gene expression programs. UltraVector-enabled matrices facilitate rapid identification of components that yield desired gene expression. Our library of characterized genetic components and associated functional characterization data enable construction of gene programs for optimized expression of multiple effector genes.
Membrane-bound interleukin-15, or mbIL15, is our proprietary chimeric cytokine that is engineered to be tethered to the cell surface to avoid systemic circulation. Expression of mbIL15 gene is shown to improve functional characteristics of certain immune cells, including T cells, by enhancing their potential for expansion and persistence resulting in longer lasting anti-tumor response.
Gene programs via viral, non-viral, and microbe-based approaches to drive lower costs
Sleeping Beauty is the leading non-viral transposon/transposase system to stably reprogram immune cells by inserting specific DNA sequences into the genome. Sleeping Beauty system brings the advantages of non-viral vectors that include the ease and relatively low cost of manufacturing, stability for longer-term storage, and lack of immunogenicity once inside host cells. Precigen has made significant improvements to the Sleeping Beauty system by optimizing gene elements, genetic payload capacity, and efficiency of delivery into the cells. These advancements have allowed us to develop a new class of autologous CAR-T therapy, UltraCAR-T, with expression of multiple effector genes simultaneously without the use of viral vectors.
AttSite recombinases enable targeted non-viral based gene delivery for various cell therapies. AttSite recombinases allow for stable integration of therapeutic genes in a unidirectional, irreversible fashion into the host cell genome. We are optimizing AttSite recombinase technology for the next generation of cutting-edge cell therapeutic applications.
AdenoVerse technology platform is composed of a library of highly potent, proprietary adenoviral vectors for efficient delivery of vaccine antigens and therapeutic genes and is built on a scalable manufacturing platform. AdenoVerse library includes our gorilla adenovectors, which provide a potential competitive advantage in their large payload capacity, ability for repeat administrations and generation of robust antigen-specific immune responses.
Lactococcus lactis, or L. lactis, is a food-grade bacterium with a long history of safe use in humans that we genetically modify to deliver biologics at local disease sites for our ActoBiotics therapeutics.
UltraPorator® is a high-throughput, semi-closed electroporation system exclusive to Precigen. The UltraPorator system includes proprietary hardware and software solutions and potentially represents major advancements over current electroporation devices by significantly reducing the processing time and contamination risk. UltraPorator is intended to be a viable scale-up and commercialization solution for decentralized UltraCAR-T manufacturing and is designed to enable rapid manufacturing for a range of gene and cell therapies beyond UltraCAR-T.
Gene expression and regulation to drive safety
The RheoSwitch Therapeutic System®, or RTS®, is the most clinically advanced gene switch system for regulation of the timing and level of gene expression in response to separately administered activator ligands, such as veledimex. The RTS® provides a mechanism to precisely control the therapeutic effect of gene and cell therapies on a patient-specific basis by modifying the timing and dose of the activator ligand.
Our suite of proprietary kill switches allow selective elimination of cell therapies in vivo via administration of a kill switch activator to improve the safety profile.
Our library of tissue-specific promoters restrict gene expression to the cells or tissues of therapeutic interest and has potential to improve safety profile of gene therapies.
Phase 1b, multicenter, single blinded, placebo-controlled, sequential dose escalation study to assess the safety and tolerability of topically applied AG013 in subjects with locally advanced head and neck cancer receiving induction chemotherapy. Limaye SA, et al. (2013) Cancer. 119:4268-4276.
A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn’s disease. Braat H, et al. (2006) Clinical Gastroenterology and Hepatology. 4:754-759.
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AG013, a mouth rinse formulation of Lactococcus lactis secreting human Trefoil Factor 1, provides a safe and efficacious therapeutic tool for treating oral mucositis. Caulwaerts S, et al. (2010) Oral Oncology. 46:564-70.
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Initial safety results and immune responses induced by a novel human papillomavirus (HPV)-specific gorilla adenovirus immunotherapy vaccine, PRGN-2009, in patients with advanced HPV-associated cancers. Floudas C, et al. Journal for ImmunoTherapy of Cancer. 2021. http://dx.doi.org/10.1136/jitc-2021-SITC2021.483.
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A gorilla adenovirus-based vaccine against Zika virus induces durable immunity and confers protection in pregnancy. Hassan, et al. (2019) Cell Reports. 28:2634-2646.
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Adenoviruses isolated from wild gorillas are closely related to human species C viruses. McVey, et al. (2013) Virology. 444:119-123.
Utilization of site-specific recombination for generating therapeutic protein producing cell lines. Campbell, et al. (2010) Molecular Biotechnology. 45:199-202. PMID: 20300883.
Phage Bxb1 integrase mediates highly efficient site-specific recombination in mammalian cells. Russell, et al. (2006) Biotechniques. 40:460, 462, 464. PMID: 16629393.
Safety of first in human triple-gene therapy candidate for heart failure patients. Jaruga-Killeen E, et al. (2019) Circulation. 140:A16296. Abstract 16296.
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Retrograde delivery of novel triple effector pDNA gene therapy for heart failure. Reed TD, et al. (2019) Mol Ther. 27(4S1):361. Abstract 775.
Human cardiac iPSC evaluation of novel triple effector gene therapy for dilated cardiomyopathy. Patel DS, et al. (2019) Mol Ther. 27(4S1):362. Abstract 777.
Minimally invasive novel triple effector gene therapy for Adriamycin cardiomyopathy. Grayburn PA, et al. (2019) Mol Ther. 27(4S1):363. Abstract 780.
Catheter-based retrograde coronary sinus infusion is a practical delivery technique for introducing biological molecules into the cardiac system. Rodenberg, et al. (2019) Catheter Cardiovasc Interv. 94:669-676. PMID: 30866153.
Genetic ataxia telangiectasia porcine model pheno copies the multisystemic features of the human disease. Beraldi, et al. (2017) Biochim Biophys Acta Mol Basis Dis. 1863:2862-2870. PMID: 28746835.
A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease. Beraldi, et al. (2015) Hum Mol Genet. PMID: 26374845.
Dystrophin exon 52-deleted pigs as a new animal model of Duchenne muscular dystrophy: its characterization and potential as a tool for developing exon skipping therapy. Echigoya, et al. (2016) Molecular Therapy: Musculo-Skeletal Diseases II. 24:S247.
H19 induces abdominal aortic aneurysm development and progression. Li, et al. (2018) Circulation. 138:1551-1568. PMID: 29669788.
Novel large animal model of xanthoma formation. Wang, et al. (2016) J Dermatol Sci. 81:203-5. PMID: 26692468.
A translational model for diet-related atherosclerosis: effect of statins on hypercholesterolemia and atherosclerosis in a minipig. Amuzie, et al. (2016) Toxicol Pathol. 44:442-9. PMID: 26883155.
Bempedoic acid lowers low-density lipoprotein cholesterol and attenuates atherosclerosis in low-density lipoprotein receptor-deficient (LDLR+/- and LDLR-/-) Yucatan miniature pigs. Burke, et al. (2018) Arterioscler Thromb Vasc Biol. 38:1178-90. PMID: 29449335.
Targeted disruption of LDLR causes hypercholesterolemia and atherosclerosis in Yucatan miniature pigs. Davis, et al. (2014) PLoS One. 9:e93457. PMID: 24691380.
Longitudinal phenotype development in a minipig model of neurofibromatosis type 1. Uthoff, et al. (2020) Scientific Reports. 19;10(1):5046. PMID: 32193437.
Assessment of nociception and related quality of life measures in a porcine model of neurofibromatosis type 1. Khanna, et al. (2019) Pain. 160:2473-86. PMID: 31246731.
A porcine model of neurofibromatosis type 1 that mimics the human disease. White, et al. (2019) JCI Insight. 3:e120402. PMID: 29925695.
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A functional anatomic defect of the cystic fibrosis airway. Birket, et al. (2014) Am J Respir Crit Care Med. 190(4):421-32. PMID: 25029666.
Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs. Stoltz, et al. (2013) J Clin Invest. 123(6):2685-93. PMID: 23676501.
CFTR-deficient pigs display peripheral nervous system defects at birth. Reznikov, et al. (2013) Proc Natl Acad Sci U S A. 110(8):3083-8. PMID: 23382208.
Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Pezzulo, et al. (2012) Nature. 487(7405):109-13. PMID: 22763554.
The ΔF508 mutation causes CFTR misprocessing and cystic fibrosis-like disease in pigs. Ostedgaard, et al. (2011) Sci Transl Med. 3(74):74ra24. PMID: 21411740.
Loss of anion transport without increased sodium absorption characterizes newborn porcine cystic fibrosis airway epithelia. Chen, et al. 2010. Cell. 143(6):911-23. PMID: 21145458.
Pigs and humans with cystic fibrosis have reduced insulin-like growth factor 1 (IGF1) levels at birth. Rogan, et al. (2010) Proc Natl Acad Sci U S A. 107(47):20571-5. PMID: 21059918.
Cystic fibrosis pigs develop lung disease and exhibit defective bacterial eradication at birth. Stoltz, et al. (2010) Sci Transl Med. 2(29):29ra31. PMID: 20427821.
Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Rogers, et al. (2008) Science. 321(5897):1837-41. PMID: 18818360.
Production of CFTR-null and CFTR-DeltaF508 heterozygous pigs by adeno-associated virus-mediated gene targeting and somatic cell nuclear transfer. Rogers, et al. (2008) J Clin Invest. 118(4):1571-7. PMID: 18324337.
Regulated intratumoral expression of IL-12 using a RheoSwitch Therapeutic System® (RTS®) gene switch as gene therapy for the treatment of glioma. Barrett, et al. (2018) Cancer Gene Therapy. 25:106-116. PMID: 29755109.
In vitro and in vivo testing of a novel regulatory system for gene therapy for intervertebral disc degeneration. Sowa, et al. (2011) Spine. 36:E623-8. PMID: 21224765.
Controlled expression of functional miR-122 with a ligand inducible expression system. Shea, et al. (2010) BMC Biotechnology. 10:76. PMID: 20961424.
Inducible mutant huntingtin expression in HN10 cells reproduces Huntington’s disease-like neuronal dysfunction. Weiss, et al. (2009) Molecular Neurodegeneration. 4:11. PMID: 19203385.
Semi-synthetic ecdysteroids as gene-switch actuators: synthesis, structure-activity relationships, and prospective ADME properties. Lapenna, et al. (2009) ChemMedChem. 4:55. PMID: 19065574.
Characterization of the RSL1-dependent conditional expression system in LNCaP prostate cancer cells and development of a single vector format. Lessard, et al. (2007) Prostate. 67:808-19. PMID: 17373718.
Phase I evaluation of PRGN-2009 alone and in combination with bintrafusp alfa in patients (pts) with recurrent/metastatic (R/M) HPV-associated cancers (HPV-C). Floudas, C.S., et al. (2023) American Society of Clinical Oncology (ASCO) Annual Meeting. Abstract 2628.
Phase 1/1b study of PRGN-3005 autologous UltraCAR-T cells manufactured overnight for infusion next day to advanced stage platinum resistant ovarian cancer patients. Liao, J.B., et al. (2023) American Society of Clinical Oncology (ASCO) Annual Meeting. Abstract 5590.
Next generation UltraCAR-T® cells with intrinsic chgeckpoint inhibition and overnight manufacturing overcome suppressive tumor microenvironment leading to sustained antitumor activity. Zenere, G., et al. (2023) American Association for Cancer Research (AACR) Annual Meeting. Abstract 1791.
Phase 1/1b Safety Study of PRGN-3006 UltraCAR-T in Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes. Sallman, D., et al. (2022) 64th Annual Meeting and Exposition of the American Society of Hematology (ASH). Abstract 4633.
A Phase1/1b Dose Escalation/Dose Expansion Study of PRGN-3007 UltraCAR-T Cells in Patients with Advanced Hematologic and Solid Tumor Malignancies. Ibarz, J., et al. (2022) 64th Annual Meeting and Exposition of the American Society of Hematology (ASH). Abstract 3334.
Incorporation of intrinsic checkpoint blockade enhances functionality of multigenic autologous UltraCAR-T cells manufactured using non-viral gene delivery and rapid manufacturing process. Chan, T., et al. (2022) American Association for Cancer Research (AACR) Annual Meeting. Abstract 2821.
Phase 1/1b Safety Study of PRGN-3006 UltraCAR-T in Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes. Sallman, D., et al. (2021) 63rd Annual Meeting and Exposition of the American Society of Hematology (ASH). Abstract 825.
Preclinical Evaluation of PRGN-3007, a Non-Viral, Multigenic, Autologous ROR1 UltraCAR-T Therapy with Novel Mechanism of Intrinsic PD-1 Blockade for Treatment of Hematological and Solid Cancers. Chan, T., et al. (2021) 63rd Annual Meeting and Exposition of the American Society of Hematology (ASH). Abstract 1694.
A Phase 1/1b Safety Study of PRGN-3006 UltraCAR-T in Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndrome. Sallman, D. et al. Blood (2020) 136 (Supplement 1): 17. 62nd Annual Meeting and Exposition of the American Society of Hematology. Abstract 2864.
PRGN-3005 UltraCAR-T: Multigenic CAR-T cells generated using non-viral gene delivery and rapid manufacturing process for the treatment of ovarian cancer. Chan, T., et al. (2020) American Association for Cancer Research (AACR) Virtual Annual Meeting II. Abstract 6593.
Preclinical characterization of PRGN-3006 UltraCAR-T for the Treatment of AML and MDS: non-viral, multigenic autologous CAR-T cells administered one day after gene transfer. Chan, T., et al. (2019) Blood. 134:2660.
Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells. Hurton, et al. (2016) Proc Natl Acad Sci U S A. 2016 Nov 29;113(48):E7788-E7797. Epub 2016 Nov 14. PMID: 27849617.
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Gene transfer efficiency and genome-wide integration profiling of Sleeping Beauty, Tol2, and piggyBac transposons in human primary T cells. Huang, et. al (2010) Mol Ther. 2010 Oct;18(10):1803-13. doi: 10.1038/mt.2010.141. Epub 2010 Jul 6. PMID: 20606646.