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.
Our lead product candidate, DSG3-CAART, is being developed to treat mucosal pemphigus vulgaris (mPV), a blistering skin disease that affects mucous membranes. mPV is caused by autoantibodies that attack the cell adhesion protein desmoglein 3, or DSG3. DSG3-CAART is designed to selectively target and kill the B cells that produce DSG3 antibodies while preserving the healthy B cells critical to immune function.
In September 2019, the FDA cleared our investigational new drug application for our clinical study of DSG3-CAART in patients with mucosal pemphigus vulgaris. We received Orphan Drug Designation for the treatment of PV from the FDA in January 2020 and Fast Track Designation for improving healing of mucosal blisters in patients with mPV from the FDA in May 2020. The DesCAARTes™ trial is actively recruiting patients at multiple clinical sites across the U.S.
The standard of care for mPV includes corticosteroids and generalized immune suppression. While these strategies may be temporarily effective, patients often expect disease recurrence and may experience severe infection, hospitalization, and a risk of death. There is a high unmet medical need for more durable and deep responses in addition to safer treatment options that can accomplish complete and lasting remission of this disease.
PV is a chronic, life-threatening autoimmune disease characterized by delamination, or separation of the layers of the skin and/or mucous membranes. Autoantibodies directed to DSG3 and/or DSG1, which are proteins expressed in desmosomes, the rivets between epithelial cells, are responsible for disease. When these desmosomes fail, erosions and blisters appear on the skin and mucosa, increasing the patient’s susceptibility to potentially fatal infections.
The pathogenic DSG3 and DSG1 autoantibodies are produced by a small number of aberrant B cells, which express the same DSG3 and DSG1 autoantibodies on their surface. These DSG-specific autoantibodies are widely considered both necessary and sufficient to cause PV.
PV has two major subtypes:
Symptoms of mPV include painful blisters on the mouth, nose, throat, genitals, and other mucosa, impairing the patient’s ability to eat, drink, or function normally.
1 Spindler, Volker, et al. "Mechanisms causing loss of keratinocyte cohesion in pemphigus." Journal of Investigative Dermatology 138.1 (2018): 32-37.
2 Schmidt, Enno, et al. "Novel ELISA systems for antibodies to desmoglein 1 and 3." Experimental dermatology 19.5 (2010): 458-463.
3 Joly, Pascal, et al. "First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomized trial." The Lancet 389.10083 (2017): 2031-2040.
4 Mouquet, Hugo, et al. "B-cell depletion immunotherapy in pemphigus: effects on cellular and humoral immune responses." Journal of Investigative Dermatology 128.12 (2008): 2859-2869.
5 Hammers, Christoph M., et al. "Persistence of anti-desmoglein 3 IgG+ B-cell clones in pemphigus patients over years." Journal of Investigative Dermatology 135.3 (2015): 742-749.
6 Lee, Jinmin., et al. "Antigen-specific B cell depletion for precision therapy of mucosal pemphigus vulgaris." The Journal of Clinical Investigation 130.12 (2020).
1 Ohyama, Bungo, et al. "Epitope spreading is rarely found in pemphigus vulgaris by large-scale longitudinal study using desmoglein 2–based swapped molecules." Journal of investigative dermatology 132.4 (2012): 1158-1168.
2 Autoantibodies that target the specific extracellular domain are shown below each extracellular domain.
DSG3-CAART preclinical data has shown selective and specific target engagement with no evidence of toxicity at clinically relevant doses.
