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

Wang, Hongjie; Liu, Ying; Li, Zong-Yi; Fan, Xiaolong LU ; Hemminki, Akseli and Lieber, Andre (2010) In Blood 115(3). p.592-600
Abstract
Many tumors, including lymphomas, upregulate 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... (More)
Many tumors, including lymphomas, upregulate 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. (Blood. 2010; 115: 592-600) (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
115
issue
3
pages
592 - 600
publisher
American Society of Hematology
external identifiers
  • wos:000273820600020
  • scopus:77449156689
ISSN
1528-0020
DOI
10.1182/blood-2009-05-222463
language
English
LU publication?
yes
id
c15c36e1-9ee6-42dc-a843-b2b2cf64fd35 (old id 1547362)
date added to LUP
2010-02-23 14:48:48
date last changed
2018-05-29 10:25:25
@article{c15c36e1-9ee6-42dc-a843-b2b2cf64fd35,
  abstract     = {Many tumors, including lymphomas, upregulate 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. (Blood. 2010; 115: 592-600)},
  author       = {Wang, Hongjie and Liu, Ying and Li, Zong-Yi and Fan, Xiaolong and Hemminki, Akseli and Lieber, Andre},
  issn         = {1528-0020},
  language     = {eng},
  number       = {3},
  pages        = {592--600},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {A recombinant adenovirus type 35 fiber knob protein sensitizes lymphoma cells to rituximab therapy},
  url          = {http://dx.doi.org/10.1182/blood-2009-05-222463},
  volume       = {115},
  year         = {2010},
}