A recombinant adenovirus type 35 fiber knob protein sensitizes lymphoma cells to rituximab therapy

Blood. 2010 Jan 21;115(3):592-600. doi: 10.1182/blood-2009-05-222463. Epub 2009 Nov 12.

Abstract

Many tumors, including lymphomas, up-regulate expression of CD46 to escape destruction by complement. Tumor cells are therefore relatively resistant to therapy by monoclonal antibodies, which act through complement-dependent cytotoxicity (CDC). From an Escherichia coli expression library of adenovirus type 35 fiber knob mutants, we selected a variant (Ad35K(++)) that had a higher affinity to CD46 than did the natural Ad35 fiber knob. We demonstrated that incubation of lymphoma cells with recombinant Ad35K(++) protein resulted in transient removal of CD46 from the cell surface. Preincubation of lymphoma cells with Ad35K(++) sensitized cells to CDC, triggered by the CD20-specific monoclonal antibody rituximab. In xenograft models with human lymphoma cells, preinjection of Ad35K(++) dramatically increased the therapeutic effect of rituximab. Blood cell counts and organ histology were normal after intravenous injection of Ad35K(++) into mice that express human CD46. The presence of polyclonal anti-Ad35K(++) antibodies did not affect the ability of Ad35K(++) to enhance rituximab-mediated CDC in in vitro assays. The Ad35K(++)-based approach has potential implications in monoclonal antibody therapy of malignancies beyond the combination with rituximab.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Adenoviridae / metabolism
  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal, Murine-Derived
  • Antigens, Viral / administration & dosage
  • Antigens, Viral / genetics
  • Antigens, Viral / metabolism
  • Antigens, Viral / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Drug Synergism
  • Humans
  • Lymphoma / drug therapy*
  • Membrane Cofactor Protein / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, SCID
  • Mice, Transgenic
  • Molecular Sequence Data
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / pharmacology*
  • Rituximab
  • Sequence Homology, Amino Acid
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • Antigens, Viral
  • Membrane Cofactor Protein
  • Recombinant Fusion Proteins
  • Rituximab