The Science

Cell Therapy: A Potentially Curative Approach to Autoimmunity

Our Opportunity

As the third most common cause of chronic illness in the U.S., autoimmune diseases affect as many as 23.5 million people1. More than 80 known autoimmune diseases exist with suboptimal treatment and no cures, representing a leading cause of death and disability.

Current therapeutic modalities include injectable monoclonal antibodies and small molecule oral medicines that do not always achieve optimal and long-lasting disease control. For example, the introduction of monoclonal antibodies targeting the TNF-alpha cytokine (also known as “anti-TNF agents”) has brought progress to the care of patients with many autoimmune diseases, yet patients often need to be switched to either another anti-TNF agent or to a new modality as disease control diminishes and symptoms return.

Autoimmune diseases may also require extreme, broadly immunosuppressive approaches (for example, corticosteroids or calcineurin inhibitors) which can leave patients with dampened immune responses, rendering them susceptible to infections and malignancies. Looking at the most recent approaches for the spectrum of immune-mediated disorders categorized as inflammatory bowel disease (IBD), up to one third of patients demonstrate primary nonresponse and another 30% of patients become refractory due to secondary loss of response.2

Kyverna aims to prove the successful application of cell therapy to autoimmunity. We believe that Kyverna’s engineered cells have the potential to address the underlying mechanisms of autoimmune disease with the additional benefits of improving safety and tolerability by minimizing toxicity associated with current treatments.

Our Opportunity Image

Potential Disease Targets

In its simplest form, autoimmune disease emerges when the complex network of the normally protective human immune system is unable to discern between self and non-self. Abnormal immunity against self-antigens may be evidenced by a rise in antibodies (called “autoantibodies”) against a variety of molecules. A cell population responsible for the production of antibodies, the B cells, has been identified as playing a key role in so-called humoral auto-immunity. Other immune cells have been identified at the root of autoimmune diseases and in particular an imbalance between T cells that dampen inflammation (regulatory T cells, or Tregs) and T cells that cause inflammation (conventional T cells, or Tconv). For these reasons, autoimmune diseases lend themselves to cell therapy treatment approaches.

Our goal is to demonstrate the clinical potential of Kyverna’s engineered T cell therapies as safe, effective, and potentially curative treatments for autoimmune diseases. Our initial disease targets are diseases for which there are no approved treatments, or for which the results of existing treatments could be further improved. In the absence of an approved treatment, physicians will often try out other medicines, exposing patients to the side-effects of these medicines with no demonstrated efficacy for the patients’ disease. This reality underscores the pressing need to come up with better solutions for patients. While treatments exist for other autoimmune diseases (e.g. Inflammatory bowel disease or IBD), a significant portion of patients are refractory and would benefit from new approaches.

Lupus Nephritis

Lupus Nephritis

What it is
An autoimmune disease for which chronic kidney inflammation can ultimately lead to complete kidney failure and the need for renal replacement.3
Where it strikes
Systemic lupus erythematosus is among the top 15 most prevalent autoimmune diseases in the U.S.1, affecting approximately 350,000 patients2. Lupus nephritis affects up to 60% of patients with systemic lupus erythematosus (SLE).
Current Treatments
There is no approved treatment for lupus nephritis. Potent immunosuppressants, dialysis, or transplantation may be proposed.
Systemic Sclerosis

Systemic Sclerosis

What it is
A multisystem autoimmune disease that is characterized by widespread vascular dysfunction and progressive fibrosis (scarring) of the skin and internal organs.
Where it strikes
The prevalence of systemic sclerosis is estimated to span from 50 to 300 cases per 1 million people.3
Current Treatments
While some treatments may alleviate symptoms, there are currently no effective or approved therapies for the underlying disease process.
Inflammatory Bowel Disease

Inflammatory Bowel Disease

What it is

Inflammatory bowel disease (IBD)4, namely ulcerative colitis and Crohn’s disease, are two distinct autoimmune diseases that involve inflammation of the gastrointestinal tract.

Where it strikes

Approximately 1.3% or 3 million U.S. adults reported being diagnosed with IBD.

Current Treatments

Several classes of agents are available in oral, injectable or local formulations. Both small and large molecules (biologics) are available. Mechanisms of action range from broad anti-inflammatory agents (e.g. corticosteroids, aminosalicylates, and JAK inhibitors) to biologic agents targeting select cytokines or addressins. Despite this plethora of approaches, few patients experience sustained disease remission.

Kyverna is developing a new class of SmarTcellTM therapies to be selective, potent, and durable with sustained therapeutic effect. By offering more than one mechanism for taming autoimmunity, Kyverna will have the opportunity to transform how autoimmune diseases are being treated.

Creating targeted cellular therapies that address the complexities of the immune system and its various types of cells

Kyverna is at the forefront of developing engineered T cell therapies for autoimmune disease by leveraging multiple approaches drawn from its SmarTcellTM Genetic Engineering Toolbox. Using our technology platforms – synReg-T cells (synthetic regulatory T cells) and synNotch CAR-T cells (chimeric antigen receptor T cells) – we are programming immune cells with instructions to suppress or eliminate pathogenic cells in the diseased tissues in which they are exerting their deleterious effects. We believe these therapies can further be designed to deliver a therapeutic payload to selected sites to reverse pathology and restore balance to the immune environment.
Creating targeted cellular therapies that address the complexities of the immune system and its various types of cells
synReg-T™ cell Platform

synReg-T cell Platform

Kyverna’s synReg-T cells are a synthetic version of Regulatory T Cells (Tregs), powerful natural immune cells that suppress autoimmune disease through multiple immunosuppressive pathways. synReg-T cells are engineered from a patient’s own lymphocytes and are genetically reprogrammed to enable them to navigate to diseased tissues and to then suppress the pathogenic properties of autoreactive immune cells. synReg-T cells can also be programmed to produce novel therapeutic molecules that further enhance their disease-modifying properties over natural Tregs.

synNotch CAR-T Platform

synNotch CAR-T Platform

Under a license agreement with Gilead/Kite, Kyverna is using synNotch technology to develop synNotch CAR-T cells (chimeric antigen receptor T cells) for autoimmune disease. The Notch receptor offers a very direct and simple mechanism of signal transduction. Engagement of the Notch receptor with its ligand releases the intracellular domain of Notch, which then acts as a transcriptional regulator.

Leveraging synNotch technology, a synthetic gene expression system that responds to specified external cues, we are engineering synNotch CAR-T cells that exploit dual receptor recognition of target cells. The synNotch technology can also be used to trigger T cell activation at a specific cell, within a specific tissue, or within an inflamed environment.

  1. Hayter et al., Autoimmune Rev., 2012 Aug;11(10):754-65.
  2. E. Carter et al., Nature Reviews Rheumatology, 12, Oct. 2016, 605-620.
  3. https://www.uofmhealth.org/conditions-treatments/rheumatology/what-scleroderma
  4. Dahlhamer JM, Zammitti EP, Ward BW, Wheaton AG, Croft JB. Prevalence of inflammatory bowel disease among adults aged ≥18 years—United States, 2015.