Enhancement of Antibody-Dependent Mechanisms of Tumor Cell Lysis by a Targeted Activator of Complement

Abstract

Complement inhibitors expressed on tumor cells provide a hindrance to the therapeutic efficacy of some monoclonal antibodies (mAb). We investigated a novel strategy to overwhelm complement inhibitor activity and amplify complement activation on tumor cells. The C3-binding domain of human complement receptor 2 (CR2; CD21) was linked to the complement-activating Fc region of human IgG1 (CR2-Fc), and the ability of the construct to target and amplify complement deposition on tumor cells was investigated. CR2 binds C3 activation fragments, and CR2-Fc targeted tumor cells by binding to C3 initially deposited by a tumor-specific antibody. Complement deposition on Du145 cells (human prostate cancer cell line) and anti-MUC1 mAb-mediated complementdependent lysis of Du145 cells were significantly enhanced by CR2-Fc. Anti-MUC1 antibody-dependent cell-mediated cytotoxicity of Du145 by human peripheral blood mononuclear cells was also significantly enhanced by CR2-Fc in both the presence and the absence of complement. Radiolabeled CR2-Fc targeted to s.c. Du145 tumors in nude mice treated with anti-MUC1 mAb, validating the targeting strategy in vivo. A metastatic model was used to investigate the effect of CR2-Fc in a therapeutic paradigm. Administration of CR2-Fc together with mAb therapy significantly improved long-term survival of nude mice challenged with an i.v. injection of EL4 cells. The data show that CR2-Fc enhances the therapeutic efficacy of antibody therapy, and the construct may provide particular benefits under conditions of limiting antibody concentration or low tumor antigen density. [Cancer Res 2007;67(19):9535-41]

Boosting antibody therapy with complement

“…They showed that human CR2-Fc is able to target to C3 activation products, enhances CDC in vitro and is effective in a mouse xenograft model. 5 The present study by Elvington et al provides data on therapeutic outcome with a murine CR2-Fc. Using 2 syngeneic mouse tumor models (metastatic lymphoma and melanoma), they demonstrate that coadministration of CR2-Fc with antitumor antibodies leads to better survival.…”

Regulation of complement and modulation of its activity in monoclonal antibody therapy of cancer

“…Complement deposition, CDC and ADCC were significantly increased in the presence of a human CR2-Fc fusion protein. 117 In vivo biodistribution studies with the radioactively-labeled fusion protein confirmed its tumor specificity. In the final therapeutic study, mice bearing EL4 T cell lymphoma were treated with a tumor-specific mAb, the fusion protein or the combination.…”

Effect of the Antibody Immunotherapy by the Anti-MUC1 Monoclonal Antibody to the Oral Squamous Cell Carcinoma in Vitro

“…CR2-Fc is able to both enhance C3 deposition with increased complement-mediated lysis and ADCC. 25) The strategy may be additive to all mAb effector mechanisms, including those that do not have ADCC and complement cytotoxicity as a recognized component of their primary mechanism of action. 25) Combination of these tools with anti-MUC1 mAb therapy may overcome OSCC and contribute to the development of strong effect and low side-effect therapy for OSCC.…”