Technology
A Next Generation Immunotherapy Platform
The Natural Killer Cell
The immune system is a tapestry of diverse families of immune cells each with its own distinct role in protecting from infections and diseases. Among these immune cells are the natural killer, or NK, cells as the body’s first line of defense. NK cells have the innate ability to rapidly seek and destroy abnormal cells, such as cancer or virally-infected cells, without prior exposure or activation by other support molecules. In contrast to adaptive immune cells such as T-cells, NK cells are uniquely powerful in that they are always activated to attack diseased cells, without a delay in killing. Our proprietary investigational activated Natural Killer (aNK) platform is based upon Natural Killer cells from a unique cell line, harnessing the power of the innate immune system.
A Unique Off-The-Shelf Targeted NK Cell Platform
Multiple Approaches to Chimeric Antigen Receptor directed killing
haNK®
Antibody-mediated killing using haNKs, which are NK cells engineered to incorporate a high binding affinity receptor that binds to an administered antibody, designed to enhance the cancer cell killing effect of that antibody.
taNK®
Chimeric Antigen Receptor directed killing using taNKs, which are NK cells engineered to incorporate chimeric antigen receptors (CARs) to target tumor-specific antigens found on the surface of cancer cells.
t-haNK™
Three modes of killing (innate, antibody mediated, and Chimeric Antigen Receptor directed killing) using t-haNKs, which are an innovative combination of our haNK and taNK platforms in a single cell.
We are developing means by which our NK cells can be grown at commercial scale as on-demand,
Living Drugs in a Bag® therapy, using our proprietary manufacturing and distribution processes.
What do we mean by Living Drugs in a Bag® therapy?
Off-the-Shelf
Designed to be used in all eligible patients
A universal cell-based therapy which doesn’t require individualized patient matching.
Eliminates a Step
No need to collect the patient’s white blood cells
With off-the-shelf aNK, this invasive procedure is eliminated.
Dosing Control
aNK’s clearance and multiple dosing may reduce the risk of adverse events, thereby producing a favorable safety profile.
Cost Effective
Economical cell therapy treatment for cancer patients
aNK can be produced in large multi-dose batches.
A New Generation of Cancer Therapy
Activated Natural Killer “Off-The-Shelf” Cells Our unique NK cell platform has been produced and utilized as a cell-based “off-the-shelf” treatment in phase 1 clinical trials, and has demonstrated tumor killing potential for cancer. Unlike normal NK cells, our unique NK cells do not express Killer Inhibitory Receptors (KIR), which diseased cells often exploit to evade the killing function of NK cells. We have optimized these unique activated NK cells, which lack these inhibitory receptors while retaining the broad array of activating receptors which enable the selective targeting and killing of diseased cells. NantKwest’s NK cells also carry a larger pay load of granzyme and perforin containing granules, thereby enabling them to deliver a far greater payload of lethal enzymes to multiple targets. Safety studies of NantKwest’s NK cells in dozens of patients treated in Phase I clinical trials have been conducted in a variety of advanced hematological malignancies and solid tumors. Encouraging evidence of safety, activity and prolonged survival have been demonstrated. Based on these clinical trials, we plan to develop the therapeutic applications of our NantKwest NK platform through genetic engineering of our NK cells to leverage the multiple modes of killing available to them, including high binding affinity antibody targeting, our haNK® platform, and tumor antigen targeting, our taNK® platform.
Manufacturing
haNK®, taNK®, t-haNK™ vs. MONOCLONAL ANTIBODIES
haNK®, taNK®, t-haNK™ vs AUTOLOGOUS CAR-T
haNK® Cells
ANTIBODY BINDING
Monoclonal antibodies bind to unique surface proteins on cancer cells
ATTACHMENT-ACTIVATION
CD16 receptors on haNK® cells attach to monoclonal antibodies previously bound to cancer cells and trigger the polarization and migration of cytolytic granules to the cancer cell target. Cytokines are also released in the process to attract and recruit additional immune cells into the area.
DEGRANULATION-DISRUPTION
Cytolytic granules discharge perforin and granzyme into synapse between the haNK® and cancer cell. Perforins punch holes in the cancer cell membrane, allowing granzymes to enter and degrade the cancer cells from the inside.
ERADICATION
Destructive enzymes break down the cell membrane and internal machinery, including the nucleus with its genetic code. The cancer cell then swells and ruptures, leaving only debris behind.
Read More
Blockbuster monoclonal antibody therapies such as Herceptin® (trastuzumab) or Rituxan® (rituximab)[1] specifically target cancer cells, thus helping to avoid adverse events that are common with chemotherapy. However, much of the cancer cell killing relies upon ADCC (antibody dependent cell-mediated cytotoxicity) whereupon effector immune cells attach to antibodies, which are in turn bound to the target cancer cell, thereby facilitating killing of the cancer by the effector cell. NK cells are the key effector cell in the body for ADCC and utilize a specialized receptor (CD16) to bind antibodies.
Studies have shown that only 10-15% of the human population uniformly expresses the “high-affinity” variant of CD16, (Musolino, et. al., J Clin Oncol, 26, 1789, 2008), which is strongly correlated with more favorable therapeutic outcomes compared to patients with the “low-affinity” CD16. Additionally, many cancer patients have severely weakened immune systems due to chemotherapy, the disease itself or other factors.
We have modified haNK cells to express high-affinity CD16. As such, haNK cells may potentiate the therapeutic efficacy of a broad spectrum of antibodies directed against cancer cells. We are actively advancing haNK and initiated our first clinical trial in July 2017.
[1] Herceptin and Rituxan are registered trademarks of Genentech.
haNK® mediates killing of HER2+ cancer cells in the presence of Herceptin
taNK® Cells
CANCER BINDING
Administered taNK® cells migrate to the site of the cancer and bind to unique surface proteins on cancer cells
ATTACHMENT-ACTIVATION
Chimeric Antigen Receptors (CARs) on taNK® cells attach to unique surface proteins on cancer cells and trigger polarization and migration of cytolytic granules to the cancer cell target. Cytokines are also released in the process to attract and recruit additional immune cells into the area.
DEGRANULATION:
Cytolytic granules discharge perforin and granzyme into synapse between the taNK® and cancer cell. Perforins punch holes in the cancer cell membrane, allowing granzymes to enter and degrade the cancer cells from the inside.
ERADICATION
Destructive enzymes break down the cell membrane and internal machinery, including the nucleus with its genetic code. The cancer cell then swells and ruptures, leaving only debris behind.
Read More
Chimeric Antigen Receptor directed killing using taNKs, which are NK cells engineered to incorporate chimeric antigen receptors (CARs) to target cancer cells displaying specific surface antigens.
taNK is a platform in which our aNK cells are engineered with one or more CARs to target proteins found on cancers and is then integrated with a wide spectrum of CARs. We believe this strategy has multiple advantages over other CAR approaches using patient or donor sourced effector cells such as autologous T-cells, especially in terms of scalability, quality control and consistency.
Our most advanced taNK cell line expresses a CAR for HER2/NEU, a protein commonly found on breast, ovary, gastric, bladder and brain cancers. Other taNK programs are in pre-IND development stages.
HER2.taNK specifically targets and kills Her2 expressing cancer cell
HER2.taNK serially kills Her2 expressing cancer cells
t-haNK™ Cells
ANTIBODY & CANCER BINDING
Monoclonal antibodies bind to unique surface proteins on cancer cells
ATTACHMENT-ACTIVATION
Polarization and migration of cytolytic granules to the cancer cell target is triggered by two independent, but synergistic pathways of a) CD16 receptors on t-haNK® cells attach to monoclonal antibodies previously bound to cancer cells and b) Chimeric Antigen Receptors (CARs), also on t-haNK® cells, attach to unique surface proteins on cancer cells. Cytokines are also released in the process to attract and recruit additional immune cells into the area.
DEGRANULATION
Cytolytic granules discharge perforin and granzyme into synapse between the t-haNK® and cancer cell. Perforins punch holes in the cancer cell membrane, allowing granzymes to enter and degrade the cancer cells from the inside.
ERADICATION
Destructive enzymes break down the cell membrane and internal machinery, including the nucleus with its genetic code. The cancer cell then swells and ruptures, leaving only debris behind.
Read More
Our newest line of product candidates are an innovative combination of our haNK and taNK platforms in a single genetic engineering that incorporates all the features of our haNK platform together with a CAR with the resulting t-hank able to avail itself of all three modes of killing: innate, antibody mediated and Chimeric Antigen Receptor directed killing. T-hank is intended to be combined with therapeutic antibodies to effectively target either two different epitopes of the same cancer specific protein or two different cancer specific proteins.
Contact us for information on NantKwest's Living Drugs in a Bag® therapy contact@nantkwest.com
