PankoMab: a potent new generation anti-tumour MUC1 antibody

Danielczyk, Antje; Stahn, Renate; Faulstich, Dorian; Löffler, Anja; Märten, Angela; Karsten, Uwe; Goletz, Steffen

doi:10.1007/s00262-006-0135-9

Cited by 112 publications

(112 citation statements)

References 40 publications

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“…The third MUC1 mAb tested, VU3C6, had specific preferences for glycosylation at the PDTR motif 27 , a common target for murine and human anti-MUC1 MAbs. 17,38,39 …”

Section: Resultsmentioning

confidence: 99%

A High-Throughput O-Glycopeptide Discovery Platform for Seromic Profiling

Blixt¹,

Cló²,

Nudelman³

et al. 2011

J. Proteome Res.

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Biomarker microarrays are becoming valuable tools for serological screening of disease-associated autoantibodies. Post-translational modifications (PTMs) such as glycosylation extend the range of protein function, and a variety of glycosylated proteins are known to be altered in disease progression. Here, we have developed a synthetic screening microarray platform for facile display of O-glycosylated peptides (O-PTMs). By introducing a capping step during chemical solid-phase glycopeptide synthesis, selective enrichment of N-terminal glycopeptide end products were achieved on an amine-reactive hydrogel coated microarray glass surface, allowing highthroughput display of large numbers of glycopeptides. Utilizing a repertoire of recombinant glycosyltransferases enabled further diversification of the array libraries in-situ and display of a new level of potential biomarker candidates for serological screening. As proof-of-concept we have demonstrated that MUC1 glycopeptides could be assembled and used to detect autoantibodies in vaccine induced disease free breast cancer patients and in patients, with confirmed disease at time of diagnosis.

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“…The third MUC1 mAb tested, VU3C6, had specific preferences for glycosylation at the PDTR motif 27 , a common target for murine and human anti-MUC1 MAbs. 17,38,39 …”

Section: Resultsmentioning

confidence: 99%

A High-Throughput O-Glycopeptide Discovery Platform for Seromic Profiling

Blixt¹,

Cló²,

Nudelman³

et al. 2011

J. Proteome Res.

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“…The cancer-specific expression of GalNAc-T6 might also interact with the immune system indirectly through induction of cancer-associated autoantibodies targeting novel cancer-specific glycopeptide epitopes (98 -102). Such site-specific glycosylation events may also represent potential targets for monoclonal antibody therapy (98,103), and our findings may provide support for the development of immunotherapeutic strategies that target aberrant O-glycoproteins or glycopeptide epitopes created by GalNAc-T6. Furthermore, the cancer-specific expression of GalNAc-T6 in colon cancer also suggests that isoform-specific inhibitors could prove useful in the future treatment of human cancers.…”

Section: Cancer-associated Expression Of Human Pp-galnac-t6mentioning

confidence: 94%

De novo expression of human polypeptide N-acetylgalactosaminyltransferase 6 (GalNAc-T6) in colon adenocarcinoma inhibits the differentiation of colonic epithelium

Lavrsen

Dabelsteen

Vakhrushev

et al. 2018

Journal of Biological Chemistry

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Edited by Eric R. FearonAberrant expression of O-glycans is a hallmark of epithelial cancers. Mucin-type O-glycosylation is initiated by a large family of UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts) that target different proteins and are differentially expressed in cells and organs. Here, we investigated the expression patterns of all of the GalNAc-Ts in colon cancer by analyzing transcriptomic data. We found that GalNAc-T6 was highly up-regulated in colon adenocarcinomas but absent in normal-appearing adjacent colon tissue. These results were verified by immunohistochemistry, suggesting that GalNAc-T6 plays a role in colon carcinogenesis. To investigate the function of GalNAc-T6 in colon cancer, we used precise gene targeting to produce isogenic colon cancer cell lines with a knockout/rescue system for GALNT6. GalNAc-T6 expression was associated with a cancer-like, dysplastic growth pattern, whereas GALNT6 knockout cells showed a more normal differentiation pattern, reduced proliferation, normalized cell-cell adhesion, and formation of crypts in tissue cultures. O-Glycoproteomic analysis of the engineered cell lines identified a small set of GalNAc-T6 -specific targets, suggesting that this isoform has unique cellular functions. In support of this notion, the genetically and functionally closely related GalNAc-T3 homolog did not show compensatory functionality for effects observed for GalNAc-T6. Taken together, these data strongly suggest that aberrant GalNAc-T6 expression and site-specific glycosylation is involved in oncogenic transformation.

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“…In fact, MUC1 vaccines were tested in several clinical trials (10)(11)(12)(13). However, they have not been as successful as hoped, in part due to the immune evasion tactics applied by tumor cells to escape immunorecognition (14,15).…”

Section: Introductionmentioning

confidence: 99%

Increased Immunogenicity of Tumor-Associated Antigen, Mucin 1, Engineered to Express α-Gal Epitopes: A Novel Approach to Immunotherapy in Pancreatic Cancer

et al. 2010

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Mucin 1 (MUC1), a bound mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic carcinoma. Evidence suggests that MUC1 can be used as a tumor marker and is a potential target for immunotherapy of pancreatic cancer. However, vaccination with MUC1 peptides fails to stimulate the immune response against cancer cells because immunity toward tumor-associated antigens (TAA), including MUC1, in cancer patients is relatively weak, and the presentation of these TAAs to the immune system is poor due to their low immunogenicity. We investigated whether vaccination with immunogenetically enhanced MUC1 (by expressing α-gal epitopes; Galα1-3Galβ1-4GlcNAc-R) can elicit effective antibody production for MUC1 itself as well as certain TAAs derived from pancreatic cancer cells and induced tumor-specific T-cell responses. We also used α1,3galactosyltransferase (α1,3GT) knockout mice that were preimmunized with pig kidney and transplanted with B16F10 melanoma cells transfected with MUC1 expression vector. Vaccination of these mice with α-gal MUC1 resulted in marked inhibition of tumor growth and significant improvement of overall survival time compared with mice vaccinated with MUC1 alone (P = 0.003). Furthermore, vaccination with pancreatic cancer cells expressing α-gal epitopes induced immune responses against not only differentiated cancer cells but also cancer stem cells. The results suggested that vaccination using cells engineered to express α-gal epitopes is a novel strategy for treatment of pancreatic cancer. Cancer Res; 70(13); 5259-69. ©2010 AACR.

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PankoMab: a potent new generation anti-tumour MUC1 antibody

Cited by 112 publications

References 40 publications

A High-Throughput O-Glycopeptide Discovery Platform for Seromic Profiling

A High-Throughput O-Glycopeptide Discovery Platform for Seromic Profiling

De novo expression of human polypeptide N-acetylgalactosaminyltransferase 6 (GalNAc-T6) in colon adenocarcinoma inhibits the differentiation of colonic epithelium

Increased Immunogenicity of Tumor-Associated Antigen, Mucin 1, Engineered to Express α-Gal Epitopes: A Novel Approach to Immunotherapy in Pancreatic Cancer

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