Off-the-Shelf NK Club Gains New Contender: Cryopreserved G-NK Cells Show Promise in Combination with Therapeutic Antibodies

January 16, 2023 / eMedClub News /--Recently,Indapta TherapeuticsAnnouncementIts research and developmentAllogeneicFcRγ-deficient natural killer (G-NK）Cell TherapyIDP-023，AlreadyIn1In the clinical trial periodCompletedFirst Batch of PatientsAdministration, forTreatment of multiple myeloma and non-Hodgkin lymphoma.The first patient received a single dose ofIDP-023, the second patient receivedIDP-023Three Scheduled DosesFirstDose. The subsequent patient cohort will receive three doses with or withoutIL-2TheIDP-023. Once the multi-dose combination was determinedIL-2The safety of the lymphoma and multiple myeloma patient cohorts will be evaluated separately.IDP-023Combination of monoclonal antibodies rituximab orDaratumumabTreatment.

Indapta's NK Cell Platform is Based on the Discovery of a Potent Subset of NK Cells—G-NK Cells. G-NK cells are present in individuals infected with cytomegalovirus and have undergone epigenetic changes.Due to the natural epigenetic changes leading to the absence of the FcRγ chain, the activity of antibody-dependent cellular cytotoxicity (ADCC) can be effectively enhanced after cross-linking with CD16.. When monoclonal antibodies bind to Fc receptors on tumor target cells and G-NK cells,Release more immune-stimulating cytokines and killer cell enzymes than conventional NK cells, directly killing tumor cells and demonstrating stronger immune-killing capabilities. They also exhibit exceptional potency in mediating ADCC (antibody-dependent cellular cytotoxicity) with excellent antibody-dependent cellular cytotoxicity and effector functions.

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Indapta believes that G-NK cells are expected to become a "best-in-class," highly safe, effective, and cost-efficient "off-the-shelf" NK cell therapy, capable of better killing cancer cells marked by therapeutic antibodies.Especially when used in combination with targeted therapies such as monoclonal antibodies or bispecific engagers of innate immunity.. In addition,By equipping G-NK cells with CAR and other targeting molecules, then combining them with monoclonal antibodies to achieve ADCC, targeting multiple cancer antigens and addressing tumor heterogeneity.. It is worth mentioning that it is also aCryopreservation products with low variability.

Dr. Mark Frohlich, CEO of Indapta Therapeutics, believes: Based on the proven clinical activity of NK cells, IDP-023 has shown better activity than conventional NK cells in preclinical models, and we look forward to further evaluating the safety and clinical activity of IDP-023 in Phase 1 trials. Indapta Therapeutics also announced,IDP-023 Production is Sufficient to Supply Phase 1 Clinical Trials Until the Second Half of 2024. Improvements in the manufacturing process will lead toIDP-023 inAchieving high yield in GMP production operations,When the product is launched, it can capture the market.Advantages in terms of product cost。

October 2022,First Cryopreserved "Off-the-Shelf" Allogeneic Blood-Derived NK Cell Therapy SNK02 Receives FDA Approval for Clinical Use to Treat Solid Tumors, composed of NK cells isolated from peripheral blood mononuclear cells of healthy donors. Unlike other cell therapies, NKGen Biotech'sSNK02 does not require lymphodepletion before administration.NKGen's proprietary allogeneic manufacturing process can produce hundreds of thousands of potential doses of NK cell therapy from materials collected from a single donor, andSNK02 cells can achieve 99% purity and very high receptor expression rates., itsMaintains significant cytotoxicity after cryopreservation, supporting its potential as an off-the-shelf candidate drug for the treatment of malignant tumors. In August 2023, NKGen Biotech announced that the first patient had been dosed in the Phase 1 clinical trial of its allogeneic, cryopreserved NK therapy, SNK02.

Celularity is dedicated to developing off-the-shelf placenta-derived allogeneic cell therapies, including unmodified NK cells, engineered NK cells, mesenchymal-like adherent stromal cells (ASC), and engineered T cells, with indications covering cancer, immunity, infectious diseases, and degenerative diseases, among others. Its lead candidate product isA Cryopreserved, Non-Gene-Modified Allogeneic NK Therapy CYNK-001, which is derived from CD34+ cells extracted from human placenta and expanded into CD56+/CD3-NK cells, has been granted Orphan Drug Designation by the FDA for the treatment of malignant glioma, as well as Fast Track Designation for the treatment of glioblastoma multiforme and leukemia. Currently, the Phase 1 clinical trial of this candidate therapy is underway.

Artiva has developed aAB-101, a cord blood-derived, allogeneic, cryopreserved, non-GMO, ADCC (antibody-dependent cell-mediated cytotoxicity) enhanced NK cell therapeutic candidate.Currently, Artiva is conducting a Phase 1/2 multicenter clinical trial to evaluate the safety and clinical activity of AB-101 alone and in combination with rituximab for the treatment of patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Meanwhile,Artiva has also partnered with Affimed N.V. to develop a combination therapy consisting of AB-101 and the innate cell engager AFM13 for the treatment of patients with relapsed/refractory CD30-positive lymphoma.The data released in 2022 shows:In 24 CD30-positive lymphoma patients receiving the Phase 2 clinical recommended dose (highest dose group), the ORR of this AFM13 combined with NK cell therapy reached 100%, and the CR reached 70.8%.

▲ AB-101 Combined with Monoclonal Antibody

（ImageSource: ArtivaOfficial Website）

In August 2023, Artiva Biotherapeutics announced that the U.S. FDA had approved itsIND Application for Allogeneic NK Therapy AB-101 (AlloNK) in Combination with Rituximab for the Treatment of Systemic Lupus Erythematosus (SLE) in Patients with Active Lupus Nephritis (LN), which marksAllogeneic NK Cell Therapy Used for the First Time in the Treatment of Autoimmune Diseases, an important step for universal cell therapy to expand its indications.

In addition,Artiva's AB-201 as a HER2-targeted allogeneic CAR-NK candidate therapy, also canSupports cryopreservation for transportation to facilitate administration in an outpatient setting.. This isThe First Systemically Administered CAR-NK Therapy for the Treatment of HER2-Positive CancersArtiva has converted a novel, high-affinity anti-HER2 antibody into an scFv structure, providing highly specific tumor targeting. Combined with its unique co-stimulatory structure and IL-15 expression design, it can enhance the activity and persistence of AB-201 in vivo.

Nkarta is also at the forefront in the field of allogeneic CAR-NK cell therapy, having advanced two products into clinical trials. NKX101, as Nkarta's lead pipeline, isA Virus-Transfected, Targeted NKG2D Ligand, Cryopreserved Allogeneic CAR-NK Cell ProductCompared with non-engineered NK cells in preclinical models, NKX101 exhibits a 10-fold increase in NKG2D expression and a 4-fold increase in cytotoxic activity. Additionally, this therapy can express membrane-bound IL-15. Another leading candidate productNKX019 is also an allogeneic, cryopreserved, off-the-shelf CAR-NK therapy.Its CAR can target CD19 on the tumor surface, and NKX019 can also express membrane-bound IL-15 to enhance the persistence and activity of the cells.

On September 22, 2023, the IND application for IBR733 Cell Injection from Yingbai Rui was accepted by the CDE. This is an allogeneic, off-the-shelf CAR-raNK cell product derived from peripheral blood, which differs from traditional CAR cells that usually use viral vectors for genetic modification.IBR733 conjugates NK cells with a CD33/CLL1 bispecific antibody., for the treatment of relapsed/refractory acute myeloid leukemia (r/r AML). Its product structure and treatment method are both international innovations, marking a significant milestone. The preliminary results of the ongoing IIT study have shown that IBR733 Cell Injection has strong potential in treating AML with good safety.

On September 14, 2023, the Phase 1 clinical trial of IBR854 Injection, a world-first innovative product developed by Indapta Therapeutics, successfully enrolled its first participant. The participant's condition was stable, with no SAE (Serious Adverse Event) reported. This candidate product received clinical trial approval in January 2023.China's first non-gene-edited CAR-raNK cell therapy for solid tumors, also a universal off-the-shelf product derived from allogeneic peripheral blood.Its core structure involves the covalent conjugation of a specific antibody targeting the tumor antigen 5T4 to allogeneic NK cells via a linker, enabling specific binding to tumor cells expressing the 5T4 target antigen, thereby achieving targeted recognition and killing of tumor cells.

On November 17, 2023, the IND for "NK Cell Injection Genetically Modified with Chimeric Antigen Receptor Targeting CD19" developed by SinoBio was accepted by the CDE, with the indication beingModerate to Severe Refractory Systemic Lupus Erythematosus. This is alsoSystemic Lupus Erythematosus Indication: China's First NK Product Receives IND AcceptanceNotably, SinoBio's CD19 CAR-NK has been deployed across multiple indications. In July,CD19 CAR-NK Granted First Official Clinical Trial Approval by CDEIntended for the treatment of adult patients with relapsed and/or refractory large B-cell lymphoma who have received at least two prior lines of systemic therapy., which marks the official entry into Phase I clinical trials of the first domestic universal NK cell therapy targeting this specific site in China.In August, the indication of CD19 CAR-NK for adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia was also approved for clinical use.

▲ SinoBio's R&D Pipeline (Source: SinoBio Official Website)

In addition, some well-known companies in China, such as Precise Bio, Sunkind Life, Genetron Biotech, Jingda Biotech, Jiyin Biotech, Heliogen Biotech, Tiankeya, and StemiX, are also actively developing universal NK therapies, creating various technologies like UCAR-NK or iPSC-CAR-NK, which are still in the early stages.