A DeImmunized chimeric anti-C3b/iC3b monoclonal antibody enhances rituximab-mediated killing in NHL and CLL cells via complement activation

Wu, Peng; Zhang, Xin; Mohamed, Nehal; Inghirami, Giorgio; Takeshita, Kenichi; Pecora, Andrew L.; Nardone, Linda L.; Pincus, Stephanie H.; Casey, Leslie S.; Spitalny, George L.

doi:10.1007/s00262-005-0686-1

Cited by 18 publications

(9 citation statements)

References 31 publications

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“…31 Further, using primary cells isolated from non-Hodgkin lymphoma and chronic lymphocytic leukemia patients, it was shown that a mouse-human chimeric mAb specific for C3b and iC3b enhanced rituximab-mediated CDC ex vivo. 32 In contrast to the current study using CR2Fc, however, there are no reports of anti-iC3b enhancing the therapeutic efficacy or outcome of mAb therapy in terms of tumor burden or survival in an in vivo model. It is also significant that CR2Fc recognizes the C3 activation products iC3b, C3dg, and C3d, whereas analysis of the anti-iC3b mAb used in the aforementioned studies revealed specificity for C3b and iC3b.…”

Section: Discussioncontrasting

confidence: 57%

A targeted complement-dependent strategy to improve the outcome of mAb therapy, and characterization in a murine model of metastatic cancer

Elvington

Huang

Morgan

et al. 2012

Blood

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Complement inhibitors expressed on tumor cells provide an evasion mechanism against mAb therapy and may modulate the development of an acquired antitumor immune response. 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 complementmediated 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 antitumor humoral or cellular immune response. CR2Fc represents a potential adjuvant treatment to increase the effectiveness of mAb therapy of cancer. (Blood. 2012;119(25):6043-6051) IntroductionComplement plays important roles in the effector mechanisms of many anticancer antibodies, 1 whether the antibodies are induced or administered. Antibody-mediated activation of complement on a tumor cell leads to cleavage of C3, a central step in the complement pathway, and results in the opsonization of the tumor cell with C3 activation products. These C3 products are recognized by complement receptors on immune effector cells and can promote and enhance complement-dependent cellular cytotoxicity (CDCC) and antibody-dependent cellular cytotoxicity (ADCC). 1 This occurs via interaction of complement receptor 3 (CR3, CD11b/CD18) with the covalently bound C3 degradation products iC3b, C3d, and C3dg. 2 Other complement activation products that may be involved in an antitumor response include the anaphylatoxins C3a and C5a, which can recruit and activate immune cells and also modulate T-cell immunity, [3][4][5] and the membrane attack complex (MAC), which can cause direct tumor cell lysis, often referred to as complement-dependent cytotoxicity (CDC). 1 Nevertheless, antibody-dependent complement activation is not, in general, an effective antitumor defense mechanism. This is thought to be the result, at least in part, of complement inhibitory mechanisms used by tumor cells. [6][7][8][9][10][11] Several studies have shown that interfering with complement inhibitor expression or function on tumor cells can enhance the effects of mAb immunotherapy in animal models. [12][13][14] In addition, complement inhibitors have been shown to modulate the outcome of both humoral and cellular immune responses, [3][4][5]15 and the down-regulation of a...

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Section: Discussioncontrasting

confidence: 57%

A targeted complement-dependent strategy to improve the outcome of mAb therapy, and characterization in a murine model of metastatic cancer

Elvington

Huang

Morgan

et al. 2012

Blood

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“…infusion of rituximab in a cynomolgus monkey model. A subsequent study by Peng et al (26) showed that a mouse/ human chimeric mAb specific for C3b and iC3b enhanced rituximabmediated killing of non-Hodgkin's lymphoma cell lines and cells isolated from non-Hodgkin's lymphoma and chronic lymphocytic leukemia patients. There is a significant potential advantage of CR2-Fc over anti-iC3b mAbs, as evidenced by its ability to significantly increase long-term survival of mice receiving mAb therapy; in the presence of serum, the initial covalently bound complement activation product C3b is very rapidly degraded to iC3b, which is in turn fairly rapidly degraded to the long-lived fragments C3dg and then C3d.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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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]

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“…This strategy has previously been shown to enhance CDC of lymphoma cell lines in vitro and to increase deposited complement when coadministered with rituximab in a cynomolgus monkey model. 3,4 Imai et al have previously introduced CR2-Fc, a fusion protein between the extracellular domain of the complement receptor 2 (CR2) and an IgG Fc domain. In contrast to antiiC3b antibodies CR2 also recognizes C3d and C3dg, the relatively long-lived complement degradation fragments.…”

Section: Boosting Antibody Therapy With Complement ------------------mentioning

confidence: 99%

“…3 In clinical trials, sorafenib has shown promising results either as a monotherapy or when combined with standard chemotherapy, with complete remissions (CRs) seen in some FLT3-ITD patients. 4 Despite the promise of sorafenib as an agent with activity against FLT3-ITD, there are many potential limitations, including initial inherent resistance to FLT3 inhibitors due to concurrent downstream pathway activation, and emergence of mutations during therapy that reduce inhibition or prevent drug binding. 2 Another important mechanism is the up-regulation of antiapoptotic Bcl-2 family members.…”

Section: Boosting Antibody Therapy With Complement ------------------mentioning

confidence: 99%

Boosting antibody therapy with complement

Boross

Leusen

2012

Blood

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A DeImmunized chimeric anti-C3b/iC3b monoclonal antibody enhances rituximab-mediated killing in NHL and CLL cells via complement activation

Cited by 18 publications

References 31 publications

A targeted complement-dependent strategy to improve the outcome of mAb therapy, and characterization in a murine model of metastatic cancer

A targeted complement-dependent strategy to improve the outcome of mAb therapy, and characterization in a murine model of metastatic cancer

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

Boosting antibody therapy with complement

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