- DSG3-CAART achieved autoantibody elimination and resolution of blisters in active immune mouse model of pemphigus vulgaris
- Soluble autoantibodies demonstrated potential to enhance DSG3-CAART efficacy and did not demonstrate off-target toxicity
- DesCAARTes™ Phase 1 clinical trial actively recruiting patients
PHILADELPHIA, Aug. 25, 2020 (GLOBE NEWSWIRE) -- Cabaletta Bio, Inc. (NASDAQ:CABA), a clinical-stage biotechnology company focused on the discovery and development of engineered T cell therapies for patients with B cell-mediated autoimmune diseases, today announced comprehensive preclinical study results evaluating DSG3-CAART (Desmoglein 3 chimeric autoantibody receptor T cells), its lead product candidate for patients with mucosal pemphigus vulgaris (mPV), were published in The Journal of Clinical Investigation. The manuscript, titled "Antigen-specific B-cell depletion for precision therapy of mucosal pemphigus vulgaris," includes the preclinical data that enabled the DSG3-CAART IND submission and opening of the DesCAARTesTM clinical trial. The paper can be accessed online at: https://www.jci.org/articles/view/138416/pdf.
The preclinical studies, conducted at the Perelman School of Medicine at the University of Pennsylvania and led by the laboratory of Aimee Payne, MD, PhD, assessed the potential toxicity and specific target engagement of DSG3-CAART in inducing antigen-specific B cell depletion. In vitro results of DSG3-CAART demonstrated specific killing of anti-DSG3 B cell receptor (BCR) expressing cell lines, as well as killing of desmoglein 3 (DSG3) specific B cells from patients with pemphigus vulgaris (PV) while sparing normal B cells. No off-target cytotoxic interactions were detected, and no DSG3-CAART activity against known binding partners to DSG3 was detected. Together the data demonstrate specific anti-DSG3 BCR killing along with a lack of on-target and off-target toxicity for DSG3-CAART.
In vivo studies included use of an active immune PV model, characterized by a PV clinical phenotype, including skin blistering and physiologic anti-DSG3 IgG levels. In these mice, DSG3-CAART reduced serum levels of pathogenic anti-DSG3 antibodies, as well as tissue bound antibodies in the epithelium, a hallmark of PV disease. Clinical and histologic resolution of blisters was observed in DSG3-CAART treated animals.
The potential impact of anti-DSG3 antibodies on DSG3-CAART toxicity and target engagement was also evaluated. The researchers studied whether anti-DSG3 antibodies could serve as a "cytotoxic bridge" enabling DSG3-CAART to kill cells which express antibody receptors on their surface, and no such cross reactivity was detected. Building on prior evidence that DSG3-CAART function is not meaningfully inhibited by anti-DSG3 antibodies, and that proliferation of DSG3-CAART in response to polyclonal PV serum IgG is observed (as previously reported in the 2016 publication in Science), the recently published studies demonstrated functional activation of DSG3 CAAR T cells in response to anti-DSG3 antibodies. This may improve the potential efficacy of DSG3-CAART in targeting rare B cells. The potential risk for CRS or other inflammatory responses resulting from DSG3-CAART interaction with soluble anti-DSG3 autoantibodies post-infusion is being mitigated in the DesCAARTesTM Phase 1 trial design through a conservative fractionated-dose approach where increasing fractions of the target dose are infused, enabling for safety monitoring between infusions while preserving the opportunity for the patient to receive a full dose.
"We believe these comprehensive preclinical data for DSG3-CAART, published in The Journal of Clinical Investigation, support our approach to develop a durable, potentially curative, treatment for patients with mucosal pemphigus vulgaris," said Steven Nichtberger, M.D., Chief Executive Officer and co-founder of Cabaletta. "CAAR T cells represent a precision therapy approach designed to eliminate the underlying cause of B cell-mediated autoimmune diseases. The data also inform development of the multiple additional CAAR T therapies for B cell-mediated diseases that are in our pipeline."
The safety and tolerability of DSG3-CAART in targeting pathogenic B cells in patients with mPV is currently being evaluated in the DesCAARTes™ clinical trial, which recently started recruiting. The FDA granted Fast Track Designation to DSG3-CAART in May 2020.