The human IgM antibody SAM-6 induces tumor-specific apoptosis with oxidized low-density lipoprotein

Brändlein, Stephanie; Rauschert, Nicole; Rasche, Leo; Dreykluft, Angela; Hensel, Frank; Conzelmann, Ernst; Müller-Hermelink, H. K.; Vollmers, H. Peter

doi:10.1158/1535-7163.mct-06-0399

Cited by 53 publications

(65 citation statements)

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“…56 In previous studies, we demonstrated that malignant cells treated with SAM-6 antibody over-accumulate lethal depots of cholesterol and triglyceride esters. 24,25 The deadly effect of SAM-6 can be increased after addition of oxidized LDL (oxLDL). 25 This non-physiological lipid accumulation was shown to be tumor specific and always resulted in tumorspecific apoptosis or lipoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…24,25 The deadly effect of SAM-6 can be increased after addition of oxidized LDL (oxLDL). 25 This non-physiological lipid accumulation was shown to be tumor specific and always resulted in tumorspecific apoptosis or lipoptosis. 24,25 The exact mechanism of SAM-6 activity is not known, but is under investigation.…”

Section: Discussionmentioning

confidence: 99%

“…24,25 Purification of SAM-6 Antibody Cell-culture supernatant was purified using cation-exchange chromatography (HiTrapt SP FF column, Amersham Bioscience, Freiburg, Germany) as described elsewhere. 25 Purity of the antibody was determined by sodium dodecylsulfate (SDS)-PAGE and activity was confirmed by immunohistochemistry and functional assays.…”

Section: Methodsmentioning

confidence: 99%

“…In a previous study, we demonstrated that SAM-6 is internalized via endocytosis and is finally responsible for a lethal accumulation of oxidized lipoproteins followed by apoptosis. 24,25 Modified protection molecules like GRP78 SAM-6 are excellent targets for specific antibodies, which not only might neutralize the protective effect of tumor cells and disable mechanisms of drug resistance, but also, as shown in this paper, directly kill the cancer cells by inducing apoptosis.…”

mentioning

confidence: 87%

“…24,25 Preliminary experiments have shown that on western blots, with membrane preparations of cancer cells the SAM-6 antibody binds to a molecule with a molecular weight of 140 kDa. 24 However, mass spectrometric analysis revealed that this band was a contamination of nuclear cell components, which was incorporated by non-optimal membrane preparation (data not shown).…”

Section: Isolation and Identification Of The Sam-6 Targetmentioning

confidence: 99%

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A new tumor-specific variant of GRP78 as target for antibody-based therapy

Rauschert

Brändlein

Holzinger

et al. 2008

Laboratory Investigation

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120

104

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The chaperone GRP78 is a member of the heat-shock protein 70 (HSP70) family and is responsible for cellular homeostasis by preventing stress-induced apoptosis. GRP78 is expressed in all cells of the body. In malignant cells, which are permanently exposed to environmental stress, GRP78 is overexpressed and increased levels can be found in the cytoplasm and on the cell membrane. Thus, GRP78 promotes tumor proliferation, survival, metastases and resistance to a wide variety of therapies. Like other tumor-specific membrane molecules, GRP78 can also be present on cancer cells in a variant form. This modification qualifies it as a target for immune surveillance and antibody responses. The fully human monoclonal IgM antibody, SAM-6, was isolated from a gastric cancer patient and it binds to a new variant of GRP78 with a molecular weight of 82 kDa. The epitope is an O-linked carbohydrate moiety and is specific for malignant cells. These data show that cancer-specific modifications of cell-surface protection molecules are (a) subject of an immune response and (b) ideal targets for new therapeutical approaches.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 87%

Section: Isolation and Identification Of The Sam-6 Targetmentioning

confidence: 99%

See 3 more Smart Citations

A new tumor-specific variant of GRP78 as target for antibody-based therapy

Rauschert

Brändlein

Holzinger

et al. 2008

Laboratory Investigation

Self Cite

120

104

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Immunoglobulins M Survive Low-pH Conditions Used for Virus Inactivation and for Elution from Bioaffinity Columns

Mueller

Wan

Hoi

et al. 2013

Journal of Pharmaceutical Sciences

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Naturally Occurring Antibodies Directed Against Carbohydrate Tumor Antigens

Schwartz‐Albiez

2012

Advances in Experimental Medicine and Biology

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Healthy persons carry within their pool of circulating antibodies immunoglobulins preferentially of IgM isotype, which are directed against a variety of tumor-associated antigens. In closer scrutiny of their nature, some of these antibodies could be defined as naturally occurring antibodies due to the germline configuration of the variable immunoglobulin region. The majority of these immunoglobulins recognize carbohydrate antigens which can be classified as oncofetal antigens. Many of these IgM antibodies present in the peripheral blood circulation can bind to tumor cells and of these a minor portion are also able to destroy tumor cells by several mechanisms, as for instance complement-mediated cytolysis or apoptosis. It was postulated that anti-carbohydrate antibodies are part of an anti-tumor immune response, while their presence in the peripheral blood of healthy donors is still waiting for a plausible explanation. It may be that recognition of defined epitopes, including carbohydrate sequences, by naturally occurring antibodies constitutes the humoral arm of an anti-tumor immune response as part of the often postulated tumor surveillance. The cytotoxic capacity of these antibodies inspired several research groups and pharmaceutical companies to design novel strategies of immunoglobulin-based anti-tumor immunotherapy.

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The human IgM antibody SAM-6 induces tumor-specific apoptosis with oxidized low-density lipoprotein

Abstract: Lipids are essential for normal and malignant cells during growth and differentiation. The turnover is strictly regulated because an uncontrolled uptake and accumulation is cytotoxic and can lead to lipoapoptosis: lipoptosis.

Cited by 53 publications

References 47 publications

A new tumor-specific variant of GRP78 as target for antibody-based therapy

A new tumor-specific variant of GRP78 as target for antibody-based therapy

Immunoglobulins M Survive Low-pH Conditions Used for Virus Inactivation and for Elution from Bioaffinity Columns

Naturally Occurring Antibodies Directed Against Carbohydrate Tumor Antigens

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