Humanized Monoclonal Antibodies and Chimeric Antigen Receptors (CAR)-T Cells that Target the Non-shed Portion of Mesothelin as Therapeutic and Diagnostic Agents

National Cancer Institute Background
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.
Technology Overview
Scientists at the National Cancer Institute (NCI) previously developed MAB15B6, an antibody that specifically bindings 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.
Further Details:

Awuah P, et al. Reduced shedding of surface mesothelin improves efficacy of mesothelin-targeting recombinant immunotoxins. [PMID 27196771]

Stage of Development

Pre-clinical (in vivo)


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


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.


The NCI seeks licensing and/or co-development research collaborations to advance the development and commercialization of these inventions for immunotherapy

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