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Optimization of highly specific SNAP-tag labeled antibody fragments and cytolytic fusion proteins for diagnosis and targeted therapy of hematopoietic malignancies

 
: Blume, T.; Fitting, J.; Stein, C.; Helfrich, W.; Fey, G.; Barth, S.

Oncology research and treatment 37 (2014), Supplement 1, pp.85
ISSN: 2296-5270
ISSN: 2296-5262
Deutscher Krebskongress <31, 2014, Berlin>
English
Abstract
Fraunhofer IME ()

Abstract
During leukemia, hematologic precursor cells suffer from an inheritable cancerogenic event (e.g. mutation), resulting in their dysfunction, buildup of immature cells and an imbalanced hematopoietic system. For future diagnosis and treatment, specificity of probes and therapeutics will be of paramount importance. Thus, our highly specific constructs for cell surface markers of leukemic blasts and leukemic stem cells are excellent therapeutic and diagnostic candidates.
To further improve the internalization and cytotoxicity, we created bivalent constructs and cytolytic fusion proteins with human effector domains for subset of constructs. We intend to enhance internalization by crosslinking of cell surface receptors upon binding. Additionally, we aim to improve the cytotoxic potential by utilizing the human effector domains Granzyme B and MAP-tau. Specific binding to the target cells as well as functionality of the Granzyme B effector domain were shown, enabling us to directly compare the constructs with the respective original immunotoxins.
Furthermore, we were able to establish a s.c. tumor in SCID mice using cells with a high sensitivity to the used immunotoxin, which exhibits a potent cytotoxicity in the nanomolar range. Determination of the maximal tolerable dose of the immunotoxin is ongoing, so far no detrimental effects were observed.
Take home message: SNAP-tag labeled antibody fragments and cytolytic fusion proteins show highly specific binding and killing of leukemic cells and thus are excellent candidates for reliable diagnosis and targeted therapy of leukemia. Their optimization regarding internalization behavior, cytotoxic potency and human immunocompatibility is currently addressed.

: http://publica.fraunhofer.de/documents/N-287191.html