Functional Characterization of an scFv-Fc Antibody that Immunotherapeutically Targets the Common Cancer Cell Surface Proteoglycan CSPG4

Wang, Xinhui; Katayama, Akihiro; Wang, Yangyang; Yu, Ling; Favoino, Elvira; Sakakura, Koichi; Favole, Adriano; Tsuchikawa, Takahiro; Silver, Susan A.; Watkins, Simon C.; Kageshita, Toshiro; Ferrone, Soldano

doi:10.1158/0008-5472.can-10-1134

Cited by 56 publications

(44 citation statements)

References 38 publications

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“…Several of the PGs that carry an rVAR2-reactive CS chain are currently being, or have been, tested as targets in clinical trials (Casucci et al, 2013; Wang et al, 2011). We propose that targeting the common CS chain present on different cancer-associated PGs may potentially offer a broad cancer targeting strategy.…”

Section: Discussionmentioning

confidence: 99%

Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein

et al. 2015

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SUMMARY Plasmodium falciparum engineer infected erythrocytes to present the malarial protein, VAR2CSA, which binds a distinct type chondroitin sulfate (CS) exclusively expressed in the placenta. Here, we show that the same CS modification is present on a high proportion of malignant cells and that it can be specifically targeted by recombinant VAR2CSA (rVAR2). In tumors, placental-like CS chains are linked to a limited repertoire of cancer-associated proteoglycans including CD44 and CSPG4. The rVAR2 protein localizes to tumors in vivo and rVAR2 fused to diphtheria toxin or conjugated to hemiasterlin compounds strongly inhibits in vivo tumor cell growth and metastasis. Our data demonstrate how an evolutionarily refined parasite-derived protein can be exploited to target a common, but complex, malignancy-associated glycosaminoglycan modification.

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Section: Discussionmentioning

confidence: 99%

Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein

et al. 2015

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“…Together with the results in other cancers this suggests CSPG4 as a promising novel therapeutic target in this tumor type. Accordingly, Wang and colleagues recently introduced a fully humanized therapeutic CSPG4 antibody that recognizes several cancer types and shows therapeutic effects in vitro and in breast cancer xenografts . Finally, targeted delivery of toxic agents to CSPG4 expressing melanoma by anti‐CSPG4‐antibodies already showed efficacy in vitro and in xenografts …”

Section: Discussionmentioning

confidence: 99%

“…Chondroitin sulfate proteoglycan 4 (CSPG4, also known as NG2/ MCSP/ HW‐MAA) is a highly glycosylated integral membrane protein, composed of an N‐linked glycoprotein‐ and a chondroitin sulfate proteoglycan‐component . Although the exact function of CSPG4 is yet unknown, it seems to be implicated in angiogenesis, tissue invasion and cell spreading …”

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confidence: 99%

Reduced promoter methylation and increased expression of CSPG4 negatively influences survival of HNSCC patients

Warta

Herold‐Mende

Chaisaingmongkol

et al. 2014

Intl Journal of Cancer

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Proteoglycans are often overexpressed in tumors and can be found on several normal and neoplastic stem cells. In this study, we analyzed in-depth the role of CSPG4 in head and neck squamous cell carcinomas (HNSCC). Analysis of CSPG4 in a homogeneous study sample of HPV-negative stage IVa HNSCCs revealed overexpression of protein and mRNA levels in a subgroup of HNSCC tumors and a significant association of high CSPG4 protein levels with poor survival. This could be validated in three publicly available microarray datasets. As a potential cause for upregulated CSPG4 expression, we identified DNA hypomethylation in a CpG-island of the promoter region. Accordingly, we found an inverse correlation of methylation and patient outcome. Finally, CSPG4 re-expression was achieved by demethylating treatment of highly methylated HNSCC cell lines establishing a direct link between methylation and CSPG4 expression. In conclusion, we identified CSPG4 as a novel biomarker in HNSCC on several biological levels and established a causative link between DNA methylation and CSPG4 protein and mRNA expression.Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer and is characterized by pathological, phenotypical and biological heterogeneity. Despite the progress in surgical and radiation techniques, the 5-year survival rate is still below 50%. 1 There is increasing evidence that epigenetic changes like DNA methylation contribute significantly to malignant transformation. Down-regulation or gene silencing caused by promoter methylation has been shown to influence tumor progression in HNSCC. 2 Chondroitin sulfate proteoglycan 4 (CSPG4, also known as NG2/ MCSP/ HW-MAA) is a highly glycosylated integral membrane protein, composed of an N-linked glycoproteinand a chondroitin sulfate proteoglycan-component. 3 Although the exact function of CSPG4 is yet unknown, it seems to be implicated in angiogenesis, tissue invasion and cell spreading. 4,5 The expression level of markers of undifferentiated cells can be accurate prognostic indicators in cancer. 6 Interestingly, there are hints that CSPG4 is expressed on normal neural stem cells and cancer stem cells of gliomas and its expression is associated with a poor prognosis and resistance to treatment. 7-11 Moreover, CSPG4 is over-expressed in epithelial tumors such as breast cancer, while in melanoma and in malignant mesothelioma it is already used for antibodybased targeted therapy. 4,12,13 As a systematic analysis of the role of CSPG4 in HNSCC is still missing, we performed an in-depth analysis of CSPG4 expression in these tumors. To prevent a potential bias in our survival analyses caused by distinct life expectations of the different TNM stages, we restricted our analyses to a more homogenous study sample consisting of HPV-negative stage IVa tumors as evidenced by p16 staining. 14, 15 We found an increased CSPG4 expression in a subgroup of HNSCCs and identified promoter methylation as regulator of CSPG4 mRNA and protein expression. Moreover, high CSPG4 expression and l...

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“…(39-43) It has been targeted with vaccines in clinical trials with no reported toxicity and anti-tumor effects have been reported in preclinical immunotherapy models with melanoma and head and neck squamous cell cancers targets. (9, 40, 44) SOX10 is a transcription factor that is expressed on neural crest cells and melanocytes, and has been shown to be crucial for the maintenance of neoplastic cells. (45, 46) In addition to being widely expressed on melanomas and other lesions such as giant congenital nevi, it has also been identified on cancers of the breast and prostate.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling using Nanostring Digital RNA Counting to Identify Potential Target Antigens for Melanoma Immunotherapy

Beard

Abate-Daga

Rosati

et al. 2013

Clinical Cancer Research

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Purpose The success of immunotherapy for the treatment of metastatic cancer is contingent on the identification of appropriate target antigens. Potential targets must be expressed on tumors but demonstrate restricted expression on normal tissues. To maximize patient eligibility, ideal target antigens should be expressed on a high percentage of tumors within a histology and potentially in multiple different malignancies. Design A Nanostring probe set was designed containing 97 genes, 72 of which are considered potential candidate genes for immunotherapy. Five established melanoma cell lines, 59 resected metastatic melanoma tumors and 31 normal tissue samples were profiled and analyzed using Nanostring technology. Results Of the 72 potential target genes, 33 were overexpressed in over 20% of studied melanoma tumor samples. Twenty of those genes were identified as differentially expressed between normal tissues and tumor samples by ANOVA analysis. Analysis of normal tissue gene expression identified 7 genes with limited normal tissue expression that warrant further consideration as potential immunotherapy target antigens: CSAG2, MAGEA3, MAGEC2, IL13RA2, PRAME, CSPG4 and SOX10. These genes were highly overexpressed on a large percentage of the studied tumor samples with expression in a limited number of normal tissue samples at much lower levels. Conclusion The application of Nanostring RNA counting technology was used to directly quantitate the gene expression levels of multiple potential tumor antigens. Analysis of cell lines, 59 tumors, and normal tissues identified 7 potential immunotherapy targets for the treatment of melanoma that could increase the number of patients potentially eligible for adoptive immunotherapy.

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Functional Characterization of an scFv-Fc Antibody that Immunotherapeutically Targets the Common Cancer Cell Surface Proteoglycan CSPG4

Cited by 56 publications

References 38 publications

Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein

Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein

Reduced promoter methylation and increased expression of CSPG4 negatively influences survival of HNSCC patients

Gene Expression Profiling using Nanostring Digital RNA Counting to Identify Potential Target Antigens for Melanoma Immunotherapy

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