Our RESETTM clinical trials with CABA-201 (investigational CD19-CAR T cell therapy) in lupus, myositis, systemic sclerosis, myasthenia gravis, and pemphigus vulgaris are now recruiting.
Engineered T cell therapy takes advantage of the T cell’s natural cell-killing capabilities. Through insertion of a gene encoding a specific receptor, these T cells are “trained” to target and destroy disease-causing cells. In the current method, T cells are sourced from a patient, modified and infused back into the same patient to take effect.
CAR (Chimeric Antigen Receptor) T cells are T cells that have been engineered with additional receptors to identify specific proteins, called antigens, present on the surface of other cells. CAR-enabled targeting is the basis of numerous oncology treatments in cancer, where CAR T cell therapy has shown remarkable clinical success.
Most CARs have a similar structure that includes an extracellular target binding domain derived from antibodies and an intracellular signaling domain derived from the natural T cell receptor complex. The extracellular domain is typically a single-chain variable fragment (scFv) that binds specifically to a target antigen on cancer cells, such as CD19. Since 2017, four CD19-specific CAR T cell products have achieved regulatory approval in B cell cancers, including in types of leukemia and lymphoma.
Over the past couple of years, academic groups have published findings demonstrating the potential of CD19-CAR T to transform the course of autoimmune disease. Emerging data in patients with systemic lupus erythematosus, myositis and systemic sclerosis suggests the potential of a one-time treatment with a 4-1BB-containing CD19-CAR T cell therapy, with a high degree of similarity to CABA-201, to achieve robust improvement in clinical disease activity within 3 months of treatment, with a favorable safety profile. Complete responses have been observed beyond 2 years with no relapses as of December 2023.
We believe that our CABA® platform – encompassing Chimeric Antigen Receptor T cells for Autoimmunity (CARTA) and Cabaletta’s proprietary Chimeric AutoAntibody Receptor T (CAART) cells – has potential applicability across a broad range of autoimmune diseases, including common and severe indications such as systemic lupus erythematosus (SLE), myositis, systemic sclerosis and generalized myasthenia gravis.
Our lead CARTA candidate, CABA-201, is a fully human CD19-CAR T cell therapy. Through transient depletion of all B cells following a single infusion, CABA-201 may be able to reset the immune system, providing potentially meaningful clinical responses to patients off immunosuppressive therapies.
The CAART product candidates employ highly specific targeting domains – custom-made for each autoimmune disease – designed to permanently eliminate only the disease-causing B cells. These B cells make up only a small fraction of all B cells, and by sparing the normal B cells, the goal is to eradicate the cause of disease while leaving the humoral immune system intact.
1Mackensen, Andreas, et al. "Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus." Nature Medicine (2022): 1-9.
2Müller, Fabian, et al. "CD19-targeted CAR T cells in refractory antisynthetase syndrome." The Lancet (2023).
3Nunez D, et al. Cytokine and reactivity profiles in SLE patients following anti-CD19 CART therapy. Mol Ther Methods Clin Dev 2023;31:101104. doi: 10.1016/j.omtm.2023.08.023.
Our team developed the Cabaletta Approach to B cell Ablation (CABA®) platform to pursue the highest priority targets where we believe there is a biologic opportunity for potential cure or paradigm-shifting treatment of autoimmune disease, broadening the potential to serve patients across several therapeutic areas.
* Illustrative list of diseases where biologic opportunity for cure or treatment with CAART or CARTA approach may be possible.
1 Koneczny, Inga. "Update on IgG4-mediated autoimmune diseases: new insights and new family members." Autoimmunity Reviews (2020): 102646.
2 Huijbers, Maartje G., et al. "IgG4-mediated autoimmune diseases: a niche of antibody-mediated disorders." Annals of the New York Academy of Sciences 1413.1 (2018): 92.
3 Ludwig, Ralf J., et al. "Mechanisms of autoantibody-induced pathology." Frontiers in immunology 8 (2017): 603.
4 Suurmond, Jolien, and Betty Diamond. "Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity." The Journal of clinical investigation 125.6 (2015): 2194-2202.
5 Xiao, Ze Xiu, Joseph S. Miller, and Song Guo Zheng. "An updated advance of autoantibodies in autoimmune diseases." Autoimmunity Reviews (2020): 102743.
6 Hampe, Christiane S. "B cells in autoimmune diseases." Scientifica 2012 (2012).
