NK Cell Therapy Gets IND FDA Clearance with AccuBase® Base Editor from KACTUS

NK Cell Therapy Gets IND FDA Clearance with AccuBase® Base Editor from KACTUS

By Mallory Griffin

November 14, 2024 Base Therapeutics announced that its independently developed NK510 cell injection, the world's first base-edited universal NK cell product, has received IND clearance from the U.S. Food and Drug Administration (FDA). The NK510 Cell Injection is intended for the treatment of advanced-stage solid tumors. KACTUS is proud to be the exclusive supplier of AccuBase® cytosine base editor, the critical raw material for the clinical manufacturing of NK510 cell injection, as well as providing regulatory support for the IND application. 

NK510 is an off-the-shelf universal NK cell therapy independently developed by Base Therapeutics. It leverages AccuBase®, a low-off-target cytosine base editor, to edit key genes in NK cells, further enhancing NK510's ability to accurately evaluate the activation and inhibition signals within the tumor microenvironment, and achieving a dual effect of overcoming cancer cell immune evasion while specifically recognizing and killing cancer cells. Currently, NK510 has demonstrated strong anti-solid tumor capabilities in multiple in vitro and in vivo preclinical studies.

Universal NK Cell Therapy with Base Editing Advantages of Base Therapeutics NK Production

Figure 1. Advantages of Base Therapeutics NK Cell Therapies [1]. 

As part of their cell therapy efforts, Base Therapeutics has successfully developed a robust process for NK cell expansion. This process enables million-fold cell expansion and stable multi-batch production. This process successfully overcomes low expansion rates and low transfection efficiency, the global challenges of allogeneic NK cell production.

About AccuBase® Cytosine Base Editor

NK510 uses AccuBase® cytosine base editor to produce genetically engineered NK cells. AccuBase® is the world’s first commercially available base editor, developed by Base Therapeutics and manufactured and distributed exclusively by KACTUS. Its high-efficiency and precise base editing capabilities have been validated across multiple cell types, achieving near-zero off-target effects. Currently, AccuBase® is available globally in both research-grade and GMP-grade, supporting the development of preclinical and clinical gene editing therapies. AccuBase® has received freedom-to-operate (FTO) designation globally. 

AccuBase® Base Editor Mechanism of Action

After forming a ribonucleoprotein (RNP) with sgRNA, AccuBase® remains in a non-editing state until it binds to the target DNA. The deaminase domain is encapsulated within the Cas9n protein, preventing interaction with non-target DNA and significantly reducing off-target effects. Upon binding to the target DNA, AccuBase® undergoes a conformational change, exposing the deaminase domain to precisely edit bases within the 3-12 window range of the target site (Figure 2). This targeted editing allows for specific point mutations (C to T or G to A) or gene knockouts by introducing premature stop codons or altering splicing sites, such as disrupting splice acceptor (SA) or splice donor (SD) sites, making it ideally suited for single-point mutation corrections or gene knockouts.

AccuBase Base Editor Mechanism of Action for base editing

Figure 2. Schematic of AccuBase® base editing mechanism. 

Advantages of AccuBase® Base Editor

  1. No Double-Stranded Breaks AccuBase® directly modifies target bases without causing double-stranded DNA breaks, unlike traditional CRISPR-Cas9/Cas12 nucleases. This avoids unexpected mutations causing genomic instability, chromosomal rearrangements, and p53 inactivation.
  2. Near-Zero Off-Target Effects The unique structural design of AccuBase® minimizes the occurrence of non-specific mutations, significantly enhancing the safety, reliability, and consistency of the editing process.
  3. High Editing Efficiency AccuBase® achieves an average editing efficiency of over 90% across randomly selected genomic loci.
  4. Broad Applicability The activity of AccuBase® has been validated on hundreds of gene loci in multiple cell lines such as human T cells, NK cells, and ESC stem cells, as well as other mammalian and fish cell lines.
  5. First Protein-Based Base Editor Nowadays, transient RNP (ribonucleoprotein) delivery has become the preferred delivery method for ex vivo gene editing. KACTUS has optimized the production process for AccuBase® enzyme, ensuring exceptional stability. Both research-grade and GMP-grade AccuBase® proteins are now available to meet quality and compliance needs at different pipeline stages.
  6. Global Patent Protection AccuBase® has obtained multiple invention patents in China, Europe, and the U.S. and has received full global freedom-to-operate (FTO) designation.
  7. International Recognition and Open Collaboration Base Therapeutics has granted non-exclusive licenses for AccuBase® base editing technology to leading CAR-T therapy companies.

Performance Validation of AccuBase® Base Editor

High Base Editing Activity 

AccuBase® RNP gene knockout efficiency in T cells using flow cytometry.

Figure 3. AccuBase® RNP was electroporated into activated primary T cells. According to flow cytometry, AccuBase® can efficiently knock out PD1, B2M, and TRAC proteins on the membrane of activated primary T cells at the protein level. For PD1 and B2M, the knockout efficiency exceeded 80%, while the knockout efficiency of TRAC reached 96%. FACS efficacy % = (positive control - KO group)/positive control* 100%. 

Near-Zero Off-Target Levels 

AccuBase near-zero off-target effects measured by GOTI versus GFP control group and control base editor

Figure 4. Measurement of off-target effects by GOTI. By leveraging the GOTI (genome-wide off-target analysis by two-cell embryo injection) to measure the off-target effects throughout the whole genome, it was shown that compared to the control base editor (with 700 SNVs detected), the number of SNV obtained after editing by AccuBase® is similar to the GFP (negative control) group, suggesting a near-to-zero off-target effects of AccuBase®. 

No DNA Insertions, Deletions, or Chromosomal Translocations

AccuBase near-zero DNA indel formation versus Cas9 protein INDELs.

Figure 5. Compared with Cas9 protein, AccuBase® does not produce DNA horizontal insertions and deletions (INDELs).

AccuBase near-zero chromosomal translocation compared to Cas9 protein.

Figure 6. Compared with Cas9 protein, AccuBase® does not cause chromosomal translocation. 

AccuBase® Product List

Catalog No.

Product Description

Available Sizes

GMP-KD-0001

AccuBase®, GMP-Grade

1mg

KD-0001

AccuBase®, Research-Grade

100μg / 500μg / 1mg

ACB-EE00B

AccuBase® ELISA Kit

96 Tests

Note: AccuBase® is the commercial name for BS-EP1.  

About Base Therapeutics

Base Therapeutics was founded in April 2021, specializing in the research and development of novel gene-editing NK cell therapy and gene therapy products.  The company operates a 2,500-square-meter GMP cell manufacturing facility and a 1,500-square-meter laboratory to meet the rigorous demands of clinical-grade cell therapy R&D and production. Base Therapeutics is conducting clinical research on its base-edited NK cell therapies to treat advanced solid and hematological tumors, including osteosarcoma, soft tissue sarcoma, non-small cell lung cancer, and acute myeloid leukemia. In addition to NK510, Base Therapeutics pipeline includes base-edited CAR-T products and in vivo base editing therapies. 

About KACTUS

KACTUS is an innovation-driven biotech specializing in recombinant proteins and enzymes for novel therapeutic development. Since its establishment in 2018, KACTUS has accumulated comprehensive experience in protein design and expression by producing high-quality engineered enzymes and complex protein targets. KACTUS operates a 10,000 m² GMP production facility and certified quality management system, manufacturing various GMP-grade proteins and enzymes for cell and gene therapy drug development. In addition to AccuBase®, KACTUS offers an off-the-shelf GMP-grade Cas9 protein and GMP-ready Cas12a protein, further supporting cell and gene therapy applications with high-quality, regulatory-compliant raw materials. 

Access More Information

For more information on AccuBase® base editor, access our brochure or visit the product page. To learn more about our gene editing product offerings, browse our Gene Editing Enzymes & Reagents.

References

  1. https://www.basetherapeutics.com/index.html#12

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