2007:"In general, monoclonal antibody immunotherapy for cancer has fallen short of clinical expectations. This is due, at least in part, to the over-expression of membrane-bound complement inhibitors on the tumor cell surface. The authors proposed to prepare and investigate the effects of two novel recombinant proteins aimed at modulating complement to increase the immune response to breast tumors. During year two it was proposed to finish construction, expression, and purification of CR2Fc; characterize the recombinant protein in vitro; and begin in vivo studies. Construction and purification of CR2Fc has been accomplished. The purification of the protein was optimized and stocks of protein have been produced for these studies. The protein has been characterized in vitro and shown to bind C3 deposited on tumor cells. Technical difficulties were encountered in vitro when looking at increased C3 deposition and tumor cell lysis but are currently being resolved. The authors will finish in vitro studies and proceed with in vivo studies to determine the effect CR2Fc has on the immune response and whether it is protective against breast tumors.
2012Mar22Epub ahead of print [Journal]Blood:
A targeted complement-dependent strategy to improve the outcome of mAb therapy, and characterization in a murine model of metastatic cancer.Elvington M, Huang Y, Morgan BP, Qiao F, van Rooijen N, Atkinson C, Tomlinson S. Department of Microbiology and Immunology, Children's Research Institute, Medical University of South Carolina, Charleston, SC,
"Complement inhibitors expressed on tumor cells provide an evasion mechanism against mAb therapy and may modulate the development of an acquired anti-tumor immune responses. Here we investigate a strategy to amplify mAb-targeted complement activation on a tumor cell, independent of a requirement to target and block complement inhibitor expression or function, which is difficult to achieve in vivo. We constructed a murine fusion protein, CR2Fc, and demonstrated that the protein targets to C3 activation products deposited on a tumor cell by a specific mAb, and amplifies mAb-dependent complement activation and tumor cell lysis in vitro. In syngeneic models of metastatic lymphoma (EL4) and melanoma (B16), CR2Fc significantly enhanced the outcome of mAb therapy. Subsequent studies using the EL4 model with various genetically modified mice and macrophage depleted mice revealed that CR2Fc enhanced the therapeutic effect of mAb therapy via both macrophage dependent Fc?R-mediated antibody-dependent cellular cytotoxicity, and by direct complement mediated lysis. Complement activation products can also modulate adaptive immunity, but we found no evidence that either mAb or CR2Fc treatment had any effect on an anti-tumor humoral or cellular immune response. CR2Fc represents a potential adjuvant treatment to increase the effectiveness of mAb therapy of cancer.
