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 immuno-oncology treatments across the biotechnology industry, 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. More recent CARs include additional costimulatory domains, such as 4-1BB (CD137), to increase the engineered cells’ cytokine production and self-replication for a more durable and potent clinical result.
Two CD19-specific CAR T cell products, Kymriah® and Yescarta®, achieved regulatory approval in 2017 for types of cancers, including acute lymphoblastic leukemia (ALL) and diffuse large B cell lymphoma (DLBCL).
In September 2022, an academic group published findings Nature Medicine that showed the potential of CD19-CAR T to transform the course of autoimmune disease. In five patients with severe systemic lupus erythematosus (SLE), one-time treatment with a 4-1BB-containing CD19-CAR T cell therapy induced clinical remission of all five patients within three months after treatment, with mild CRS in 3/5 patients and no neurotoxicity observed. Healthy B cells repopulated in all patients within 5 months of treatment, and responses remained durable off all SLE-associated medications with 5-17 months of follow-up.1 Similar results were observed in a case report of a patient with anti-synthetase syndrome, a subtype of myositis, as published The Lancet in February 20232. These findings demonstrate the potential for CD19-CAR T to “reset the immune system,” potentially eliminating the cause of autoimmune disease with restoration of the healthy immune system.
® These names are the registered trademarks of Novartis and Gilead Sciences, respectively.
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 dozens of autoimmune diseases, including common and severe indications such as systemic lupus erythematosus (SLE), rheumatoid arthritis, myositis and systemic sclerosis.
Our lead CARTA candidate, CABA-201, is based on a clinically-evaluated fully human CD19 binder containing a 4-1BB co-stimulatory domain. Through potential transient depletion of all B cells following a single infusion, CABA-201 may be able to reset the immune system by eliminating disease-causing B cells and allowing repopulation by healthy B cells, providing potentially meaningful clinical responses to patients without long-term immunosuppression.
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 leave the humoral immune system intact while eradicating the cause of disease.
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).
3Ellebrecht, Christoph T., et al. "Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease." Science 353.6295 (2016): 179-184.
Our team developed the Cabaletta Approach to B cell Ablation (CABA™) platform to identify autoimmune diseases and to pursue the highest priority targets for our technology.
* 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).
