Effect of a novel fully human monovalent antigen-binding fragment on the survival of cancer cell lines

Oncol Rep. 2007 Aug;18(2):513-7.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine having potent cytotoxic activity specifically to tumor cells. Agonistic antibodies against TRAIL receptors are currently being explored as anti-cancer therapeutics. Here, we report studies on JKTR-18, a monovalent human monoclonal antibody Fab selected against human recombinant TRAIL receptor 2 (DR5) by phage display technology. It induced cell death in Jurkat and HL60 leukemia cell lines without the need for secondary crosslinkers in vitro. It did not compete with soluble TRAIL (sTRAIL) for binding to DR5, and its combination with sTRAIL resulted in greater cell death than either agent alone. The cell death induced by JKTR-18 included a caspase-independent mechanism. This is the first report of a monovalent antibody fragment against TRAIL receptor that can induce tumor cell death in the absence of a crosslinker.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Amino Acid Sequence
  • Antibodies, Monoclonal / genetics
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology*
  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Caspase Inhibitors
  • Cell Survival / drug effects
  • Cysteine Proteinase Inhibitors / pharmacology
  • DNA Fragmentation / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • HL-60 Cells
  • Humans
  • Immunoglobulin Fab Fragments / genetics
  • Immunoglobulin Fab Fragments / immunology
  • Immunoglobulin Fab Fragments / pharmacology*
  • Jurkat Cells
  • Leukemia / metabolism
  • Leukemia / pathology
  • Molecular Sequence Data
  • Protein Binding / immunology
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / immunology*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • Time Factors

Substances

  • Amino Acid Chloromethyl Ketones
  • Antibodies, Monoclonal
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • Immunoglobulin Fab Fragments
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • Caspase 3
  • Caspase 7