CMML (chronic myelomonocytic leukemia) belongs to the group of myeloid neoplasms known as myelodysplastic and myeloproliferative diseases. In some patients with a history of CMML, the disease transforms to acute myelomonocytic leukemia (AMML). There are no specific treatment options for patients suffering from CMML except for supportive care and DNA methyltransferase inhibitors in patients with advanced disease. New treatment strategies are urgently required, so we have investigated the use of immunotherapeutic directed cytolytic fusion proteins (CFPs), which are chimeric proteins comprising a selective domain and a toxic component (preferably of human origin to avoid immunogenicity). The human serine protease granzyme B is a prominent candidate for tumor immunotherapy because it is expressed in cytotoxic T lymphocytes and natural killer cells. Here, we report the use of CD64 as a novel target for specific CMML and AMML therapy, and correlate CD64 expression with typical surface markers representing these diseases. We demonstrate that CD64-specific human CFPs kill CMML and AMML cells ex vivo, and that the mutant granzyme B protein R201K is more cytotoxic than the wild-type enzyme in the presence of the granzyme B inhibitor PI9. Besides, the human CFP based on the granzyme B mutant was also able to kill AMML or CMML probes resistant to Pseudomonas exotoxin A. What's new? New treatment strategies for chronic (CMML) and acute myelomonocytic leukemia (AMML) are urgently needed. This study suggests that CD64 is not only a promising diagnostic marker but also a novel target for specific CMML and AMML therapy. The data show that CD64-specific human cytolytic fusion proteins kill CMML and AMML cells ex vivo, with the mutant granzyme B protein R201K being more cytotoxic than its wild type in the presence of the granzyme B inhibitor PI-9. GbR201K-H22(scFv) also shows superior activity to a state-of-the-art anti-CD64 immunotoxin based on Pseudomonas exotoxin A on PI-9-positive and negative primary CMML and AMML cells. Copyright © 2014 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.
CITATION STYLE
Schiffer, S., Rosinke, R., Jost, E., Hehmann-Titt, G., Huhn, M., Melmer, G., … Thepen, T. (2014). Targeted ex vivo reduction of CD64-positive monocytes in chronic myelomonocytic leukemia and acute myelomonocytic leukemia using human granzyme B-based cytolytic fusion proteins. International Journal of Cancer, 135(6), 1497–1508. https://doi.org/10.1002/ijc.28786
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