scholarly journals A chondroitin sulfate proteoglycan 4‑specific monoclonal antibody inhibits melanoma cell invasion in a spheroid model

2021 ◽  
Vol 59 (3) ◽  
Author(s):  
Karolina Uranowska ◽  
Mahzeiar Samadaei ◽  
Tanja Kalic ◽  
Matthias Pinter ◽  
Heimo Breiteneder ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Chondroitin Sulfate ◽  
Melanoma Cell ◽  
Cell Invasion ◽  
Chondroitin Sulfate Proteoglycan ◽  
Sulfate Proteoglycan ◽  
Specific Monoclonal Antibody ◽  
Proteoglycan 4

Immunotoxin and bcl-2 inhibitor combination therapy targeting chondroitin sulfate proteoglycan 4.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 74-74
Author(s):  
Xin Yu ◽  
Stephen T. Keir ◽  
Scott Szafranski ◽  
Steven Clayton ◽  
Ira Pastan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Combination Therapy ◽  
Chondroitin Sulfate ◽  
Cell Lines ◽  
Melanoma Cell ◽  
Chondroitin Sulfate Proteoglycan ◽  
Breast Cancer Cell Lines ◽  
Sulfate Proteoglycan ◽  
Proteoglycan 4 ◽  
Melanoma Cell Lines

74 Background: Immunotoxins (ITs) are a class of bifunctional chimeric proteins composed of an antibody fragment linked to a toxin. When ITs internalize into target cells, they induce protein synthesis inhibition and apoptosis. While ITs are highly specific and potent, the efficacy of IT-based therapies in some tumor cells is limited by hyperactive anti-apoptotic pathways and inefficient translocation of ITs from the endoplasmic reticulum to the cytosol. Therefore, to improve the efficacy of IT-based therapies, we evaluated a dual-pathway therapy that combines an IT with the ABT-737, ABT-263, or ABT-199 small molecule Bcl-2 inhibitor. Methods: The immunotoxin 9.2.27-PE38KDEL (9.2.27-IT) was generated by fusing a truncated mutant form of Pseudomonas exotoxin A to a single-chain variable fragment antibody. It targets human chondroitin sulfate proteoglycan 4 (CSPG4), an antigen highly expressed in a variety of cancer cells. We screened and identified 3 human glioblastoma xenografts, 3 human melanoma cell lines, and 5 human breast cancer cell lines resistant to the 9.2.27-IT despite their high levels of cell surface expression of CSPG4 (IC50 of IT alone was >100 ng/ml in all cell lines except for one melanoma cell line). In vitro cytotoxicity of the 9.2.27-IT —alone or in combination with the individual Bcl-2 inhibitors ABT-737, ABT-263, or ABT199—was assessed. Concentrations of ABT analogues were chosen so that ABT alone did not induce cytotoxicity. Results: The treatment groups that responded to the combination therapy yielded IC50 values ranging from 0.04 – 9 ng/ml for glioblastoma xenografts, 0.21-15 ng/ml for melanoma cell lines, and 4.5-50 ng/ml for breast cancer cell lines. The most potent combination group showed >1000 fold improvement of IC50 compared to using the immunotoxin alone. ABT-737 produced the strongest synergistic effects among the ABT analogues. Preliminary results from in vivo studies further demonstrated that this approach engendered a synergistic response and delayed tumor growth in immunotoxin-resistant mouse tumor models. Conclusions: This new combinatorial approach will potentially help to overcome immunotoxin resistance in cancer patients and provide better therapeutic outcomes.

Identification of Chondroitin Sulfate Proteoglycan-4 In Acute Myeloid Leukemia Using Monoclonal Antibody 225.28

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4885-4885
Author(s):  
Moon Fenton ◽  
Maura Gasparetto ◽  
Chang-Sook Hong ◽  
XinHui Wang ◽  
Clay Smith ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Chondroitin Sulfate ◽  
Conflicts Of Interest ◽  
Chondroitin Sulfate Proteoglycan ◽  
Potential Candidate ◽  
Sulfate Proteoglycan ◽  
Malignant Cells ◽  
Npm1 Mutation ◽  
Cytogenetic Abnormalities ◽  
Proteoglycan 4

Abstract Abstract 4885 Chondroitin sulfate proteoglycan-4 (CSPG4) is a membrane-bound proteoglycan that is expressed on the surface of differentiated malignant cells, progenitor cells, and cancer initiating cells in various types of solid tumors. CSPG4 is highly conserved through evolution; its structure, amino acid sequence and functional properties show a high degree of homology with its rat counterpart, named neuron-glial antigen 2 (NG2). CSPG4 has been shown to be involved in the activation of several signaling pathways that play an important role in tumor progression. Because of its high levels of expression on malignant cells and its restricted distribution in normal tissues, CSPG4 is potential candidate tumor marker and target for immune- and targeted therapy. CSPG4 has been shown previously to be expressed on AML cells using an antibody raised against the rat counterpart and levels of expression were correlated with the clinical course of the disease. In this report we extend these findings by identifying a monoclonal antibody (mAb) directed at a human CSPG4 epitope and then used this antibody to examine co-expression with other common markers in AML as well as important molecular/cytogenetic abnormalities. Initially we screened a panel of 15 CSPG4-specific mAb which recognize 7 distinct epitopes for reactivity with leukemic blasts. mAb 225.28 was shown to have the highest reactivity and was selected for further studies. CSPG4 expression using mb225.28 was detected in 18/18 peripheral blood samples containing AML blasts at levels ranging from 0.2% to 98%. 7 samples showed less than 10% CSPG4 positive cells, 2 showed 10 – 20% positivity, 4 showed 20 – 30% positivity, and 5 showed greater than 30% positivity. CSPG-4 expression was not confined to any single blast sub-population defined by co-staining with CD34, CD117 and CD33. The expression of CSPG4 was shown on leukemic cells with mixed lineage leukemia (MLL) gene rearrangements, FTL3 mutation, NPM1 mutation, and complex cytogenetic abnormalities. These results indicate that the expression of CSPG4 is not restricted to any sub-type of AML or confined to one developmental compartment and using the mAb 225.28 CSPG4 may constitute a potential marker for AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Chondroitin Sulfate Proteoglycan 4 and Its Potential As an Antibody Immunotherapy Target across Different Tumor Types

2018 ◽  
Vol 8 ◽  
Author(s):  
Kristina M. Ilieva ◽  
Anthony Cheung ◽  
Silvia Mele ◽  
Giulia Chiaruttini ◽  
Silvia Crescioli ◽  
...  
Keyword(s):  
Chondroitin Sulfate ◽  
Chondroitin Sulfate Proteoglycan ◽  
Sulfate Proteoglycan ◽  
Proteoglycan 4 ◽  
Antibody Immunotherapy ◽  
Immunotherapy Target ◽  
Tumor Types
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