CFR-1 receptor as target for tumor-specific apoptosis induced by the natural human monoclonal antibody PAM-1

Brändlein, Stephanie; Pohle, Tina; Vollmers, Christopher; Wozniak, Ewa; Ruoff, Nele; Müller‐Hermelink, Hans Konrad; Vollmers, H. Peter

doi:10.3892/or.11.4.777

Cited by 16 publications

(16 citation statements)

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“…Glycosylation may also modulate protein processing and hence affect exposure of new epitopes as shown in Rasmussen's encephalitis, where an N-glycan blocks proteolysis of a neuronal glutamate receptor and the establishment of a short peptide epitope [40]. Several human monoclonal antibodies have been shown to be directed to epitopes affected by glycosylation [41][42][43][44][45] but it is currently unclear if these antibodies define glycopeptide epitopes per se. The O-glycopeptide autoantibody epitopes identified on human MUC1 and murine podoplanin are therefore important models for this type of epitope.…”

Section: Discussionmentioning

confidence: 98%

Characterization of an immunodominant cancer-specific O-glycopeptide epitope in murine podoplanin (OTS8)

et al. 2010

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Auto-antibodies induced by cancer represent promising sensitive biomarkers and probes to identify immunotherapeutic targets without immunological tolerance. Surprisingly few epitopes for such auto-antibodies have been identified to date. Recently, a cancer-specific syngeneic murine monoclonal antibody 237, developed to a spontaneous murine fibrosarcoma, was shown to be directed to murine podoplanin (OTS8) with truncated Tn O-glycans. Our understanding of such cancer-specific auto-antibodies to truncated glycoforms of glycoproteins is limited. Here we have investigated immunogenicity of a chemoenzymatically produced Tn-glycopeptide derived from the putative murine podoplanin O-glycopeptide epitope. We found that the Tn O-glycopeptide was highly immunogenic in mice and produced a Tn-glycoform specific response with no reactivity against unglycosylated peptides or the O-glycopeptide with extended O-glycan (STn and T glycoforms). The immunodominant epitope was strictly dependent on the peptide sequence, required Tn at a specific single Thr residue (Thr(77)), and antibodies to the epitope were not found in naive mice. We further tested a Tn O-glycopeptide library derived from human podoplanin by microarray analysis and demonstrated that the epitope was not conserved in man. We also tested human cancer sera for potential auto-antibodies to similar epitopes, but did not detect such antibodies to the Tn-library of podoplanin. The reagents and methods developed will be valuable for further studies of the nature and timing of induction of auto-antibodies to distinct O-glycopeptide epitopes induced by cancer. The results demonstrate that truncated O-glycopeptides constitute highly distinct antibody epitopes with great potential as targets for biomarkers and immunotherapeutics.

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Section: Discussionmentioning

confidence: 98%

Characterization of an immunodominant cancer-specific O-glycopeptide epitope in murine podoplanin (OTS8)

et al. 2010

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“…5) [36,37,41]. PAM-1 inhibits tumor growth in vitro and in animal systems, by inducing apoptosis [55].…”

Section: Natural Antibodies and Cancermentioning

confidence: 99%

Natural antibodies and cancer

Vollmers

Brändlein

2007

Journal of Autoimmunity

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“…Antibody PAM-1 derived from a patient with stomach cancer identifies a variant of the cysteine-rich fibroblast growth factor receptor 1 (CFR-1) and inhibits cell growth and induces apoptosis. 80 SAM-6 binds to a cell surface receptor and to oxidized low-density lipoprotein (LDL). 71 The antibody/LDL complex is internalized, lipid depots are formed and cytochrome c is released from mitochondria followed by activation of caspases.…”

Section: Mechanisms Of Cell Lysismentioning

confidence: 99%

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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CFR-1 receptor as target for tumor-specific apoptosis induced by the natural human monoclonal antibody PAM-1

Cited by 16 publications

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Characterization of an immunodominant cancer-specific O-glycopeptide epitope in murine podoplanin (OTS8)

Characterization of an immunodominant cancer-specific O-glycopeptide epitope in murine podoplanin (OTS8)

Natural antibodies and cancer

Naturally Occurring Antibodies Directed Against Carbohydrate Tumor Antigens

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