Chimeric Antigen Receptors (CAR)-T Cells that Target the Non-Shed Portion of Mesothelin as a Therapeutic Agent

Mesothelin (MSLN) is an excellent target for antibody-based therapies of cancer because of its high expression in many malignancies but lack of expression on essential normal tissues. Unfortunately, a large fragment of MSLN is shed from cancer cells, causing the currently available anti-MSLN antibodies (and immunoconjugates thereof) which bind to the shed portion of MSLN to quickly lose their therapeutic effectiveness over time. Indeed, the shed portion of MSLN can act as a decoy for these antibodies, further limiting them from reaching and destroying tumor cells.

Scientists at NCI previously developed MAB15B6, an antibody that specifically binds to the unshed region of MSLN and blocks MSLN shedding. Building on this discovery, the inventors made specific modifications to CARs which utilize humanized MAB15B6.  T cells expressing these enhanced CARs are very active in blocking tumor progression in xenograph models. As a result, these CAR-T cells represent an excellent therapeutic candidate for patients who have not responded to other MSLN-targeted therapeutics.

Competitive Advantages:

• The inventors have made specific improvements to immunoconjugates which utilize MAB15B6 that significantly enhance the ability of these immunoconjugates to exert a therapeutic effect
• Specific binding to the unshed portion of MSLN allow the antibodies and CAR-T cells to maintain contact with the cancer cells for a longer duration to exert a therapeutic effect
• More effective in blocking tumor progression compared to currently available anti-MSLN antibodies

Commercial Applications:

• Treatment of MSLN-positive malignancies such as synovial sarcoma, mesothelioma, and ovarian, lung, esophageal, pancreatic and gastric cancers
• Therapeutic Use as a targeting moiety for CARs, antibody-drug conjugates (ADCs), immunotoxins (RITs), bispecific antibodies, etc.