Expansion of natural killer cells in mice transgenic for IgM antibody to ganglioside GD2: demonstration of prolonged survival after challenge with syngeneic tumor cells

Kawashima, Ichiro; Yoshida, Yasuko; Taya, Chouji; Shitara, Hiroshi; Yonekawa, Hiromichi; Karasuyama, Hajime; Tada, Nobuhiko; Furukawa, Koichi; Tai, Tadashi

doi:10.3892/ijo.23.2.381

Cited by 8 publications

(8 citation statements)

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“…Their mechanism(s) of action is not clear, but a recent study in which mice transgenic for anti-GD2 IgM antibody were protected from EL4 metastasis and death indicated a role for IgM, complement and NK cells (55). In the current study, we show that in contrast to IgG therapy, the therapeutic effect of IgM was complement dependent, because the protective effect of anti-GD2 IgM was completely abolished in C3-deficient mice.…”

Section: Discussionmentioning

confidence: 52%

Complement-Mediated Mechanisms in Anti-GD2 Monoclonal Antibody Therapy of Murine Metastatic Cancer

et al. 2005

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The role of complement in antibody therapy of cancer is in general poorly understood. We used the EL4 syngeneic mouse model of metastatic lymphoma to investigate the role of complement in immunotherapy directed against GD2, a target of clinical relevance. IgG2a and IgM anti-GD2 therapy protected EL4-challenged mice from metastases and prolonged survival. Expression of CD59, an inhibitor of direct complementmediated cytotoxicity (CMC), effectively protected EL4 cells from CMC in vitro but did not affect the outcome of monoclonal antibody therapy. Protection by IgG therapy was also unaffected in mice deficient in C3 or complement receptor 3 (CR3) but was almost completely abrogated in Fc;R I/III-deficient mice. These data indicate a crucial role for antibody-dependent cell-mediated cytoxicity (ADCC). However, at lower doses of IgG, therapeutic effect was partially abrogated in C3-deficient mice, indicating complement-mediated enhancement of ADCC at limiting IgG concentration. In contrast to IgG, the therapeutic effect of IgM was completely abrogated in C3-deficient mice. High level expression of CD59 on EL4 did not influence IgM therapy, suggesting IgM functions by complement-dependent cell-mediated cytotoxicity (CDCC), a mechanism thought to be inactive against tumor cells. Thus, IgG and IgM can operate via different primary mechanisms of action, and CDCC and complement-dependent enhancement of ADCC mechanisms are operative in vivo. The effects of complement can be supplemental to other antibody-mediated mechanisms and likely have increased significance at limiting antibody concentration or low antigen density. (Cancer Res 2005; 65(22): 10562-8)

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Section: Discussionmentioning

confidence: 52%

Complement-Mediated Mechanisms in Anti-GD2 Monoclonal Antibody Therapy of Murine Metastatic Cancer

et al. 2005

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“…3). Given that anticarbohydrate IgM antibody suppresses cancers in vivo (29), HMMC-1 could potentially exhibit anticancer activity in vivo. Due to the i.p.…”

Section: Discussionmentioning

confidence: 99%

HMMC-1

Nozawa¹,

Aoki²,

Tsukazaki³

et al. 2004

Clinical Cancer Research

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Purpose: The purpose of this research was to generate a human monoclonal antibody specific to gynecological cancers and to evaluate such an antibody as therapy for gynecological cancers.Experimental Design: Transchromosomal KM mice were immunized with the human uterine endometrial cancer cell line SNG-S. Hybridomas were constructed between spleen cells from KM mice and mouse myeloma cells. Reactivity of the antibody was evaluated by immunohistochemistry of pathological specimens of gynecological cancers. Cytotoxicity of HMMC-1 against SNG-S cells was tested by in vitro cytotoxicity assays. The epitope of HMMC-1 was determined by transfection with a panel of glycosyltransferase cDNAs and by inhibition assays with chemically synthesized oligosaccharides.Results: HMMC-1 is a human IgM monoclonal antibody that reacts positively with mü llerian duct-related carcinomas with positive rates of 54.6% against uterine endometrial adenocarcinoma, 76.9% against uterine cervical adenocarcinoma, and 75.0% against epithelial ovarian cancer. HMMC-1 does not react with normal endometrium at proliferative or secretory phases, normal uterine cervix, or normal and malignant tissue from other organs, whereas it reacts weakly with the epithelium of the gall bladder and the collecting duct of the kidney. HMMC-1 exhibits antigendependent and complement-mediated cytotoxicity. Upon cotransfection with cDNAs encoding two glycosyltransferases required for fucosylated extended core 1 O-glycan, mammalian cells express HMMC-1 antigen. Finally, binding of HMMC-1 to SNG-S cells is inhibited by synthetic Fuc␣132Gal␤134GlcNAc␤133Gal␤133GalNAc␣1-octyl.Conclusions: These results indicate that HMMC-1 specifically recognizes a novel O-glycan structure. The unique specificity and cytotoxicity of HMMC-1 strongly suggest a therapeutic potential of this antibody.

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“…Clinical studies have indicated a role for anti-ganglioside IgM antibodies (including anti-GD2) in passive and active immunity against some cancers [ 148 , 149 , 150 ]. Their mechanism(s) of action is not clear, but a study in which mice transgenic for anti-GD2 IgM antibody were protected from EL4 metastasis and death indicated a role for IgM, complement and NK cells [ 151 ]. In these studies depletion of NK cells with anti-asialo GM1 rabbit serum reduced or abrogated the observed anti-tumor effects, suggesting that NK cells play a major role in tumor eradication or suppression [ 151 ].…”

Section: Innate Recognition Of Glycans That Lends To Tumor Suppresmentioning

confidence: 99%

“…Their mechanism(s) of action is not clear, but a study in which mice transgenic for anti-GD2 IgM antibody were protected from EL4 metastasis and death indicated a role for IgM, complement and NK cells [ 151 ]. In these studies depletion of NK cells with anti-asialo GM1 rabbit serum reduced or abrogated the observed anti-tumor effects, suggesting that NK cells play a major role in tumor eradication or suppression [ 151 ]. It is possible that the GD2 model actually opens a window on a more general innate circuitry, which has just been further elucidated.…”

Section: Innate Recognition Of Glycans That Lends To Tumor Suppresmentioning

confidence: 99%

Tumor-Associated Glycans and Immune Surveillance

2013

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Changes in cell surface glycosylation are a hallmark of the transition from normal to inflamed and neoplastic tissue. Tumor-associated carbohydrate antigens (TACAs) challenge our understanding of immune tolerance, while functioning as immune targets that bridge innate immune surveillance and adaptive antitumor immunity in clinical applications. T-cells, being a part of the adaptive immune response, are the most popular component of the immune system considered for targeting tumor cells. However, for TACAs, T-cells take a back seat to antibodies and natural killer cells as first-line innate defense mechanisms. Here, we briefly highlight the rationale associated with the relative importance of the immune surveillance machinery that might be applicable for developing therapeutics.

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Expansion of natural killer cells in mice transgenic for IgM antibody to ganglioside GD2: demonstration of prolonged survival after challenge with syngeneic tumor cells

Cited by 8 publications

References 0 publications

Complement-Mediated Mechanisms in Anti-GD2 Monoclonal Antibody Therapy of Murine Metastatic Cancer

Complement-Mediated Mechanisms in Anti-GD2 Monoclonal Antibody Therapy of Murine Metastatic Cancer

HMMC-1

Tumor-Associated Glycans and Immune Surveillance

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