High-Fidelity AaCas12bMAX Enables the Development of an Engineered T Cell Therapy with Enhanced Safety and Functional Fitness

Fig 1. Article HighlightsOverview

Fig 3. AaCas12b^MAXAndSpCas9EditedTILComparison of Product Functions

Thanks to the extensive data and mature processes accumulated through Grail Biotechnology's self-developed KOReTIL® high-efficiency gene knockout platform, the research team efficiently completed the entire process from conceptualization to publication of results. The KOReTIL® platform offers advantages such as high-efficiency gene knockout (>90%), multi-target parallel validation, stable amplification, and industrial scalability. Leveraging this technology, Grail Biotechnology has successfully edited and functionally validated over a hundred immune suppression targets and filed more than 50 international patents. The preliminary achievements of the KOReTIL® platform have provided strong support for sgRNA screening, editing safety research framework construction, and product process development in this project.

We sincerely thank Zhuhai Shutong Medical Technology Co., Ltd. and Nanjing Nadgene Biotechnology Co., Ltd. for their strong support as co-authors of this research; we also thank NEB Protein (Suzhou) Co., Ltd. for providing AaCas12b.^MAXEnzymes support this research and product development.

Original link:

https://doi.org/10.1016/j.ymthe.2025.09.009

References:

1. Krishna, S., Lowery, F.J., Copeland, A.R., Bahadiroglu, E., Mukherjee, R., Jia, L., Anibal, J.T., Sachs, A., Adebola, S.O., Gurusamy, D., et al. (2020). Stem-like CD8 T cells mediate response of adoptive cell immunotherapy against human cancer. Science 370, 1328-1334. 10.1126/science.abb9847.

Grail Bio was founded in 2019 as an innovative pharmaceutical company focused on tumor immunotherapy, with a research and development pipeline represented by TIL drugs. Grail Bio has completed multiple rounds of equity financing, receiving support from several well-known venture capital funds. GT101 Injection, independently developed by Grail Bio, is China's first TIL drug approved for registrational clinical trials and has now entered the pivotal Phase II clinical trial. GT201 Injection, Grail Bio’s TIL product featuring the world's first membrane-bound IL-15 complex, has completed IND applications in both China and the U.S. and has been approved to enter Phase I clinical trials.

The company's core R&D platforms include the StemTexp® dry TIL expansion technology platform, StaViral® virus stable cell line process, ImmuT Finder® immunomodulatory target discovery platform, and KOReTIL® high-efficiency gene knockout system. Based on these platforms, a series of next-generation gene-edited TIL drugs have been developed. Grit Bio has internationally leading technical reserves and industry resources, aiming to create groundbreaking solid tumor cell therapies, bringing new hope to cancer patients worldwide. For more information, please visit: www.grit-bio.com。

Shanghai Tianze Yuntai Biomedical Co., Ltd. was registered in Shanghai, China in March 2020. It is committed to transforming cutting-edge gene and cell therapy technologies into clinically accessible treatment methods, with the aim of benefiting more patients.

Shanghai Tianze Yuntai Biomedical Co., Ltd. owns proprietary intellectual property rights to the ViVec® AAV vector screening platform, ViLNP® lipid nanoparticle technology platform, ViCas® CRISPR gene editing technology platform, and ViHiYi® AAV high-yield technology platform. By employing strategies such as gene replacement, gene regulation, and gene editing, the company develops innovative gene therapies for central nervous system diseases, metabolic and hematological disorders, and ophthalmic diseases, with a diversified pipeline that includes multiple potential First-in-class products. To date, Shanghai Tianze Yuntai has received multiple rounds of investment from several well-known funds. It has established a 2,500-square-meter gene therapy R&D and operations center in Zhangjiang High-Tech Park, a gene editing technology R&D center in Beijing's Nest.Bio Lab, a 3,000-square-meter pilot production workshop for gene therapy in Lingang Special Area, and a 9,500-square-meter GMP commercial production facility in Waigaoqiao Free Trade Zone.

Professor Li Wei, the scientific founder of Shanghai Tianze Yuntai Biomedical Co., Ltd., was the first internationally to report that modified Cas12b can achieve gene editing in mammalian systems. This is the third highly efficient mammalian genome editing tool following Cas9 and Cas12a. Shanghai Tianze Yuntai has exclusively licensed the related technology patents for this gene editing tool and has since refined them for both industrial and clinical applications. Based on this, the company has developed its proprietary multi-scenario ViCas® CRISPR editing technology platform, which includes VG-Cas12b.^Max、VG-Cas12i^Max、VG-Cas12iHiFiEfficient editors capable of recognizing multiple PAM sequences, proprietary gRNA scaffolds, stabilization site-specific modification strategies, highly active editor recombinant proteins, and mRNA-LNP editing systems. Based on these, the company not only builds its own rich gene-editing product pipeline but also provides other cell and gene therapy companies with this new generation of highly efficient, low off-target gene-editing tools to address the issue of core gene-editing tool patents being monopolized by the United States.