Kyverna is on the forefront of developing advanced cellular therapies designed to be selective, potent, and durable with sustained therapeutic effect. Our therapeutic platform leverages T cell engineering and synthetic biology technologies to target the underpinnings of autoimmunity: CAR T cells (chimeric antigen receptor T cells), synReg T cells (synthetic regulatory T cells) and synNotch CAR T cells. By offering more than one mechanism for taming autoimmunity, Kyverna will have the opportunity to transform how autoimmune diseases are treated.
Creating “smarter” CAR T cells
Leveraging advances in CAR T engineering and insights from the use of conventional CAR T cell therapies for cancer, Kyverna is building a robust collection of cell therapy assets and tools to address multiple targets implicated in the pathogenesis of autoimmune diseases.
Targeted cellular therapies that address the complexities of the immune system and its various disease mechanisms
CAR T cells with the potential for therapeutic breakthrough in B-cell driven autoimmune diseases.
Kyverna is the exclusive world-wide licensee of a next-generation CAR T construct targeting CD19 for use in autologous (KYV-101) and allogeneic (KYV-201) cell therapies for B-cell driven autoimmune diseases. Designed with favorable characteristics for use in autoimmunity, KYV-101 and KYV-201 combine a fully human anti-CD19 CAR with costimulatory domains designed to minimize cytokine release and improve clinical tolerability.
In a 20-patient Phase 1/2 study in oncology, expected anti-lymphoma activity was associated with a significant reduction of cytokines released. Of note, in patients who received the new construct, a ten-fold reduction in the rate of severe neurological toxicity was observed compared to patients who received T cells transduced with an earlier generation, murine-based construct.1
Preclinically, CD19-targeted CAR T-cell therapies have been shown to induce deep and complete B cell depletion in both the circulation and tissues resulting in striking efficacy in disease models supporting the promise of a transformative impact for the approach in patients with B-cell driven autoimmune diseases.2 B cells are important for disease pathogenesis, and tissue-based B cells are resistant to depletion by existing agents. Overall, existing approaches to address B-cell driven autoimmune diseases are often limited by either modest effects, leading to resistant and uncontrolled disease, or significant treatment-related morbidity and mortality.
Prior generations of anti-CD19 CAR T cells rely on mouse-derived CD19 binding domains and are associated with high levels of cytokine production. Importantly, high cytokine production has been shown to translate to cytokine release syndrome.3 In contrast, KYV-101 and KYV-201 use a fully human anti-CD19 CAR and costimulatory domains designed to minimize cytokine production. These two combined attributes are of particular importance for use in autoimmune disease patients because (i) autoimmune disease patients are known to mount immune reactions against foreign mouse proteins and (ii) the cytokines released in high amounts by traditional CAR T cells are the same cytokines that can drive autoimmune diseases. The impact our anti-CD19 CAR has had on reducing clinically relevant immunogenicity and on minimizing the production of disease-driving cytokines has been extensively characterized.1
Kyverna intends to advance the autologous version of this novel CD19 construct, KYV-101, into clinical development for autoimmune diseases in the first half of 2022.
- Brudno J et al. Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma. Nature Medicine 2020;26:270-280.
- Kansal R et al. Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus. Science Translational Medicine 2019; 11(482):eaav1648.
- Frigault et. al. State of the art in CAR T cell therapy for CD19+ B cell malignancies. JCI 2020; 130(4):1586-1594.
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 mechanisms. synReg T cells are engineered from patient T lymphocytes and are genetically reprogrammed to enable them to navigate to diseased tissues and to then suppress the pathogenic properties of autoreactive immune cells. We anticipate that in the future synReg T cells could also be engineered from healthy donor T lymphocytes. In addition, synReg T cells can be programmed to produce novel therapeutic molecules that further enhance their disease-modifying properties over natural Tregs.
Under a license agreement with Gilead/Kite, Kyverna is using the synNotch technology to develop synNotch CAR T cells (chimeric antigen receptor T cells) for autoimmune diseases. The synNotch receptor offers a very direct and simple mechanism of signal transduction. Engagement of the synNotch receptor with its ligand releases the intracellular domain of synNotch, which then acts as a transcriptional regulator to control the expression of a second circuit component, such as a CAR receptor. Leveraging synNotch technology, a synthetic gene expression system that responds to specified external cues, we are engineering synNotch CAR T cells with a logic circuit to recognize pathogenic cells. The synNotch technology can be used to trigger T cell activation at a specific cell, within a specific tissue, or within an inflamed environment.