A recombinant adenovirus type 35 fiber knob protein sensitizes lymphoma cells to rituximab therapy.
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.
Wang
Hongjie
H
Division of Medical Genetics, University of Washington, Seattle, USA.
Liu
Ying
Y
Li
Zong-Yi
ZY
Fan
Xiaolong
X
Hemminki
Akseli
A
Lieber
André
A
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D058846:Antibodies, Monoclonal, Murine-Derived; D000956:Antigens, Viral / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004357:Drug Synergism; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy*; D051916:Membrane Cofactor Protein / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D000069283:Rituximab; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000956:Antigens, Viral; D051916:Membrane Cofactor Protein; D011993:Recombinant Fusion Proteins; D000069283:Rituximab