Journal
MOLECULAR THERAPY
Volume 21, Issue 2, Pages 291-299Publisher
CELL PRESS
DOI: 10.1038/mt.2012.212
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Funding
- National Institutes of Health (NIH) [R01 CA080192, R01 HLA078836, R43 CA162582]
- Washington State Life Science Discovery Fund
- Washington Research Foundation
- Institute for Translational Health Sciences at the University of Washington
- National Primate Research Center at the University of Washington, NIH grant [RR00166]
- National Center for Research Resources
- Office of Research Infrastructure Programs of the NIH through Grant [OD 010425]
- Deutsche Krebshilfe [108988]
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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.
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