Model DSG3-CAART - Potential Treatment Under Development for Patients with Mucosal Pemphigus Vulgaris (mPV)
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.
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Disease Suppression, Not Immunosuppression
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.
About Pemphigus Vulgaris (PV)
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:
- Mucosal PV (mPV)—Characterized by DSG3 autoantibodies, affecting primarily mucosal surfaces—accounts for approximately 25% of patients with PV.
- Mucocutaneous PV (mcPV)—Characterized by DSG3 and DSG1 autoantibodies, affecting both mucosal and skin surfaces—accounts for approximately 75% of patients with PV.
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.
Why DSG3 is an Optimal Candidate for PV
- DSG3 autoantibodies are widely considered to be necessary and sufficient to cause mPV.1
- Serum anti-DSG3 autoantibodies are 98 – 100% sensitive and specific.2
- Depletion of B cells by rituximab3 or antibody by plasmapheresis transiently improves clinical disease.
- Incomplete B cell depletion by rituximab leads to PV recurrences, with identical disease-causing B cell clones.4,5
- The B cell repertoire and antigenic epitopes on DSG1/3 are well understood6 and formed the basis for DSG3 and DSG1 CAAR designs.
- The DSG3 CAAR has published animal model proof-of-concept validation.
Preclinical Data
DSG3-CAART preclinical data has shown selective and specific target engagement with no evidence of toxicity at clinically relevant doses.
Target Engagement
Anti-DSG3 Autoantibody Titer
- Serologic ‘remission’ - dose-dependent elimination of anti-DSG3 B cells and autoantibodies
CAAR T Cell Engraftment
- Dose-dependent increase in CAAR-positive cells observed via flow cytometry
Tissue Blistering
- Histologic ‘remission’ - no blistering of oral mucosa
Anti-DSG3 Hybridoma Outgrowth
- Significantly delayed outgrowth despite soluble anti-DSG antibodies
Active Immune Model
- Target engagement despite presence of physiologic DSG3 antibody titer
Tolerability
In Vitro & In Vivo Assessments of Tolerability
- No specific cytotoxicity at clinically relevant cell numbers vs. Fc-gamma receptor-expressing cells
- No confirmed interactions with human membrane proteins
- No off-target effects detected at clinically relevant doses
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