Abstract
We have developed a novel antibody-drug conjugate (ADC) that can selectively deliver the Lck inhibitor dasatinib to human T lymphocytes. This ADC is based on a humanized antibody that selectively binds with high affinity to CXCR4, an antigen that is selectively expressed on hematopoietic cells. The resulting dasatinib-antibody conjugate suppresses T-cell-receptor (TCR)-mediated T-cell activation and cytokine expression with low nM EC50 and has minimal effects on cell viability. This ADC may lead to a new class of selective immunosuppressive drugs with improved safety and extend the ADC strategy to the targeted delivery of kinase inhibitors for indications beyond oncology.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies / chemistry*
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Dasatinib / administration & dosage*
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Dasatinib / chemistry
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Dasatinib / pharmacology
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HEK293 Cells
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Humans
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Immunoconjugates / administration & dosage
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Immunoconjugates / chemistry*
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Immunosuppressive Agents / administration & dosage
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Immunosuppressive Agents / chemistry*
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Immunosuppressive Agents / pharmacology
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors
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Receptors, CXCR4 / immunology
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Receptors, CXCR4 / metabolism
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T-Lymphocytes / drug effects*
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Trastuzumab / immunology
Substances
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Antibodies
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CXCR4 protein, human
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Immunoconjugates
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Immunosuppressive Agents
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Receptors, CXCR4
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
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Trastuzumab
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Dasatinib