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Targeted ex vivo reduction of CD64‐positive monocytes in chronic myelomonocytic leukemia and acute myelomonocytic leukemia using human granzyme B‐based cytolytic fusion proteins
Author(s) -
Schiffer Sonja,
Rosinke Reinhard,
Jost Edgar,
HehmannTitt Grit,
Huhn Michael,
Melmer Georg,
Barth Stefan,
Thepen Theo
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28786
Subject(s) - granzyme b , chronic myelomonocytic leukemia , granzyme , biology , immunology , myeloid leukemia , cytotoxic t cell , fusion protein , leukemia , cancer research , granzyme a , medicine , bone marrow , myelodysplastic syndromes , cd8 , perforin , immune system , recombinant dna , biochemistry , gene , in vitro
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.