The exact function of differentiation antigen mesothelin (MSLN) is unclear, but scientists know it is typically expressed in mesothelial cells in the pleural, pericardium, and peritoneum. Mesothelin is highly expressed in several human cancers, including mesotheliomas, pancreatic adenocarcinomas, and approximately 70% of ovarian cancers and 50% of lung adenocarcinomas. Preclinical and clinical studies have shown that overexpression of mesothelin can promote tumor cell proliferation and invasion. While these factors indicate that mesothelin could be a promising target for cancer therapy, antibody-based drugs targeting mesothelin have either shown limited therapeutic effect or caused severe adverse events.
Description
Due to its remarkable success in treating B cell malignancies, CAR-T cell therapy has become a potential strategy for treating MSLN-expressing tumors. Safety issues, adverse events, and tolerated dose of MSLN-targeting CAR-T cell therapy are currently being evaluated in multiple phase I and II clinical trials. University of Pittsburgh researchers have identified a panel of 12 fully human single-VH domains for use in CAR-T cell therapy against MSLN-expressing tumors, which are expected to have less immunogenicity than those currently in clinical trials. The small size of these engineered antibody domains (eAds) could contribute to better penetration efficiency and broader applicability than previous antibody therapies, with the additional ability to target cryptic epitopes that are otherwise occluded by full-length antibodies and with enhanced access to some epitopes and expression.
Applications
· Treating MSLN-expressing cancers
Advantages
· May elicit a less severe immune response than current antibody therapies
· Small size allows enhanced access and penetration of tumors
· Preliminary results indicate high binding activities and resistance to aggregation
· Cross-reactive to both human and rhesus macaque mesothelin
· Lack of non-specific binding
· Flexibility in application, including CAR-T cell therapies
Invention Readiness
In vitro data
IP Status
https://patents.google.com/patent/US20240034807A1
