title: Transient removal of CD46 is safe and increases B-cell depletion by rituximab in CD46 transgenic mice and macaques.
abstract: We have developed a technology that depletes the complement regulatory protein (CRP) CD46 from the cell surface, and thereby sensitizes tumor cells to complement-dependent cytotoxicity triggered by therapeutic monoclonal antibodies (mAbs). This technology is based on a small recombinant protein, Ad35K++, which induces the internalization and subsequent degradation of CD46. In preliminary studies, we had demonstrated the utility of the combination of Ad35K++ and several commercially available mAbs such as rituximab, alemtuzumab, and trastuzumab in enhancing cell killing in vitro as well as in vivo in murine xenograft and syngeneic tumor models. We have completed scaled manufacturing of Ad35K++ protein in Escherichia coli for studies in nonhuman primates (NHPs). In macaques, we first defined a dose of the CD20-targeting mAb rituximab that did not deplete CD20-positive peripheral blood cells. Using this dose of rituximab, we then demonstrated that pretreatment with Ad35K++ reconstituted near complete elimination of B cells. Further studies demonstrated that the treatment was well tolerated and safe. These findings in a relevant large animal model provide the rationale for moving this therapy forward into clinical trials in patients with CD20-positive B-cell malignancies.
authors.affiliation: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Ines
authors.initials: I
authors.lastname: Beyer
authors.forename: Hua
authors.initials: H
authors.lastname: Cao
authors.forename: Jonas
authors.initials: J
authors.lastname: Persson
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Roma
authors.initials: R
authors.lastname: Yumul
authors.forename: Zongyi
authors.initials: Z
authors.lastname: Li
authors.forename: Douglas
authors.initials: D
authors.lastname: Woodle
authors.forename: Ronald
authors.initials: R
authors.lastname: Manger
authors.forename: Michael
authors.initials: M
authors.lastname: Gough
authors.forename: Diane
authors.initials: D
authors.lastname: Rocha
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Bogue
authors.forename: Audrey
authors.initials: A
authors.lastname: Baldessari
authors.forename: Ronald
authors.initials: R
authors.lastname: Berenson
authors.forename: Darrick
authors.initials: D
authors.lastname: Carter
authors.forename: André
authors.initials: A
authors.lastname: Lieber
mesh_terms: D000074323:Alemtuzumab; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology / Q000494:pharmacology*; D018951:Antigens, CD20 / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008212:Lymphocyte Depletion; D008251:Macaca; D051916:Membrane Cofactor Protein / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D000069283:Rituximab; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; C497859:Mcp protein, mouse; D051916:Membrane Cofactor Protein; D000074323:Alemtuzumab; D000069283:Rituximab; D000068878:Trastuzumab