TECHNOLOGY

Allogeneic Natural Killer Cells Engineered to Beat Autoimmune Diseases

TARGETING AUTOIMMUNE DISEASE AT ITS ROOT

As part of the innate immune system, natural killer (NK) cells constitute a powerful first line of defense against dysfunctional, diseased or otherwise abnormal B cells. NK cells constantly patrol the body to identify and kill abnormal cells that could be harmful to healthy tissue. They do this by recognizing markers of stress on the surface of problematic cells, independent of the antigens they display. This allows NK cells to target a wider range of disease-causing cells than T cells, which are white blood cells that only target cells that display specific antigens, and makes them ideal for targeting the pathogenic B cells that are at the root of many autoimmune diseases. To boost the natural ability of NK cells to find and eliminate their targets, Nkarta’s cell therapy candidate adds a chimeric antigen receptor (CAR) to target B cells.

ELIMINATING PROBLEMATIC AUTOANTIBODIES

Normal B cells help the body fight infection by producing antibodies that target antigens from viruses, bacteria and other pathogens. Abnormal B cells are the main culprits in many autoimmune diseases because they secrete autoantibodies that can work against the patient’s own body to cause the patient’s immune system to attack healthy tissue. Clinical studies have shown that deep depletion of B cells can address autoimmune disease by reducing or eliminating the offending B cells that produce these autoantibodies, allowing normal B cells to replenish. This “immune reset” could offer patients the possibility of achieving long-lasting remission.

Nkarta’s first CAR NK cell program, NKX019, is engineered with a CAR targeting CD19 found on pathogenic B cells. By eliminating B cells and initiating this reset, our cells have the potential to transform the standard of care for patients with B cell-mediated autoimmune diseases such as lupus nephritis (LN), systemic sclerosis (SSc), inflammatory myopathy (IMM), antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and other autoimmune diseases.

What is systemic lupus erythematosus?

Systemic lupus erythematosus (SLE) is an autoimmune disease that causes the body’s immune system to attack its own tissues. The dysregulated immune system produces autoantibodies that can affect various organs, including the skin, joints, kidneys, heart and brain.

SLE can cause lupus nephritis, a severe complication that occurs when the immune system mistakenly attacks the kidneys, leading to inflammation and potential organ damage and kidney failure.

What is primary membranous nephropathy?

Primary membranous nephropathy (pMN) is an autoimmune disease that causes the body’s immune system to attack the filters of the kidneys. Unlike lupus nephritis, pMN arises on its own and is not caused by SLE.

What are inflammatory myopathies?

Inflammatory myopathies, also known as idiopathic inflammatory myopathies, are a group of autoimmune conditions characterized by inflammation of muscle and other organ systems often resulting in organ failure.

What is ANCA associated vasculitis?

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an umbrella term for a group of rare autoimmune conditions that cause inflammation of blood vessels.

What is systemic sclerosis?

Systemic sclerosis (SSc) is a chronic disease of the connective tissue where its rapid growth causes scarring of skin and internal organs. SSc is most common in women and most often develops around age 30 to 50.

ENGINEERING FOR ENHANCED EFFECTIVENESS

NK cells have intrinsic properties that make them attractive candidates for cell therapies to treat B cell-mediated autoimmune diseases:

  • They are immediately effective upon administration
  • They can infiltrate tissues in the body where B cells are found

Through advanced engineering, we enhance the effectiveness and persistence of donor NK cells in the patient’s body with two key features:

  • A CAR designed to target CD19, a surface protein expressed by B cells that cause autoimmune disease
  • Membrane-bound IL-15, a cytokine (immune-signaling protein) that promotes the activity and persistence of NK cells

These features are engineered intentionally to enable our CAR NK cell therapy to recognize and eliminate B cells without help from other immune cells. This initiates the immune reset that allows normal B cells, but not pathogenic B cells, to replenish.

CAR-NK cell with highlights of the CAR and mbIL-15 receptors

Targeting receptor, OX40 costimulatory
domain, CD3ζ signaling moiety,
membrane bound IL-15

DELIVERING SAFETY ADVANTAGES

Our CAR NK cells are infused at the therapeutic doses intended to eliminate pathogenic B cells. Because they don’t have to expand in the body to be effective, the risk of severe side effects, such as CRS or ICANS are greatly reduced. Other safety advantages of our CAR NK cell therapies include:

  • No risk of causing graft-versus-host disease (GvHD) – a common complication with other allogeneic cell therapies – because NK cells lack the markers that could trigger GvHD
  • Clearance from the body in a matter of weeks

INCREASING ACCESS TO THERAPY WITH ALLOGENEIC CAR NK CELLS

NKX019 has the potential to reach a broader patient population for three reasons:

  1. It is made from healthy donors’ cells, sparing patients the inconvenience of leukapheresis (cell-collecting procedure) and treatment delays associated with autologous cell therapies
  2. It has a highly favorable profile that reduces the need to monitor the patient for toxicities after administration
  3. They can be manufactured at scale and made available for outpatient administration

Nkarta’s goal is to offer patients with B cell-mediated autoimmune diseases the life-changing treatment options they deserve by providing effective, safe and accessible CAR NK cell therapies.

Nkarta’s off-the-shelf Manufacturing From Healthy Donor cells

Manufacturing steps: Collect & Isolate; Activate; Engineer; Expand; Cryopreserve; Thaw & Administer

1 | Collect

NK cells are collected from healthy donors by leukapheresis.

2 | Activate

NK cell expansion using our proprietary growth process.

3 | Engineer

Expanded NK cells are genetically programmed to express membrane-bound IL-15 and CAR.

4 | Expand

Continued expansion driven by the introduced membrane-bound IL-15.

5 | Cryopreserve

Harvesting and cryopreservation of final cell product.

6 | Thaw & Administer

NK cells are thawed for off-the-shelf administration to patients at the time they need it.