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.
Background on CAR T CellsCAR (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. The intracellular domain most commonly incorporates CD3 Zeta, a primary component of the natural T cell receptor that triggers the release of cytotoxins, which kill the target cell. 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). While these products provide deep and durable responses for many patients with certain B cell-related cancers, their design results in the complete elimination of cancerous as well as all normal protective B cell populations, which can be associated with well-described side effects.
® These names are the registered trademarks of Novartis and Gilead Sciences, respectively.
Our scientific founders hypothesized that a modest modification to the CAR T cell technology platform could result in a highly targeted killing profile, which might spare the normal B cell population and reduce the risk of adverse events.
Our CAAR (Chimeric AutoAntibody Receptor) is designed to be identical to the CAR in a currently marketed and FDA-approved CAR T cell therapy except in the extracellular domain, where it is engineered to encode the specific antigen targeted by disease-causing autoantibodies. Unlike the antibodies in a healthy humoral immune system, autoantibodies, or antibodies against self-proteins, are the pathogenic agents in some types of autoimmune diseases. Because these autoantibodies are also expressed on the surface of the pathogenic B cells that produce them, the CAAR on the T cells is designed to trap and destroy these B cells, eliminating the cause of disease. This intended exquisite specificity contrasts with currently approved CAR T products, which target all CD19-expressing cells, including the normal and the cancer-causing B cells. Our CAAR T cells are designed to kill only a small fraction of all B cells and to spare the normal B cells that are needed for protection from infection, which we believe may lead to a more favorable tolerability profile.
CAR T (left) and CAAR T therapy (right) differ in the extracellular targeting domain: CAR T cells contain antibody fragments in the targeting domain, which recognize proteins on the surface of pathogenic cells; conversely, CAAR T cells contain autoantigens, the target of autoantibodies, in the targeting domain. Called “autoantibody receptors,” these autoantigens are recognized by disease-causing autoantibodies and the pathogenic B cells that produce them. Cabaletta’s CAAR T cells contain the same signaling and co-stimulatory domains as a currently marketed and FDA-approved CAR T cell therapy, which trigger the release of cytokines and enhance cytokine production and T cell replication, respectively.
Our team developed the Cabaletta Approach to selective B cell Ablation (CABA™) platform to identify B cell-mediated autoimmune diseases and pursue the highest priority targets for our technology.
