title: An immunosuppressive antibody-drug conjugate.
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.
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology and ‡Department of Immunology and Microbial Science, The Scripps Research Institute , La Jolla, California 92037, United States.
authors.forename: Rongsheng E
authors.initials: RE
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.forename: Jintang
authors.initials: J
authors.lastname: Du
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: Luo
authors.forename: Vishal
authors.initials: V
authors.lastname: Deshmukh
authors.forename: Chan Hyuk
authors.initials: CH
authors.lastname: Kim
authors.forename: Brian R
authors.initials: BR
authors.lastname: Lawson
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Tremblay
authors.forename: Travis S
authors.initials: TS
authors.lastname: Young
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Kazane
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
mesh_terms: D000906:Antibodies / Q000737:chemistry*; D000069439:Dasatinib / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000737:chemistry*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors; D019718:Receptors, CXCR4 / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000068878:Trastuzumab / Q000276:immunology
chemical_list: D000906:Antibodies; C527276:CXCR4 protein, human; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D019718:Receptors, CXCR4; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D000068878:Trastuzumab; D000069439:Dasatinib