CSPG4: A Target for Selective Delivery of Human Cytolytic Fusion Proteins and TRAIL

Abstract

Chondroitin-sulfate proteoglycan 4 (CSPG4) is a transmembrane glycoprotein overexpressed on malignant cells in several cancer types with only limited expression on normal cells. CSPG4 is implicated in several signaling pathways believed to drive cancer progression, particularly proliferation, motility and metastatic spread. Expression may serve as a prognostic marker for survival and risk of relapse in treatment-resistant malignancies including melanoma, triple negative breast cancer, rhabdomyosarcoma and acute lymphoblastic leukemia. This tumor-associated overexpression of CSPG4 points towards a highly promising therapeutic target for antibody-guided cancer therapy. Monoclonal αCSPG4 antibodies have been shown to inhibit cancer progression by blocking ligand access to the CSPG4 extracellular binding sites. Moreover, CSPG4-directed antibody conjugates have been shown to be selectively internalized by CSPG4-expressing cancer cells via endocytosis. CSPG4-directed immunotherapy may be approached in several ways, including: (1) antibody-based fusion proteins for the selective delivery of a pro-apoptotic factors such as tumor necrosis factor-related apoptosis-inducing ligand to agonistic death receptors 4 and 5 on the cell surface; and (2) CSPG4-specific immunotoxins which bind selectively to diseased cells expressing CSPG4, are internalized by them and induce arrest of biosynthesis, closely followed by initiation of apoptotic signaling. Here we review various methods of exploiting tumor-associated CSPG4 expression to improve targeted cancer therapy.

Electroporation-Based Treatments in Small Animal Veterinary Oral and Maxillofacial Oncology

“…CSPG4 is a transmembrane glycoprotein that is overexpressed on malignant cells of different tumors and involved in promoting oncogenic transformations, enabling proliferation, motility and metastatic spread of malignant cells via various modes of action. CSPG4 has been recognized as a marker for aggressive, therapy-resistant cancers and simultaneously serves as a target for tumor-selective oncolytic agents [reviewed by Jordaan et al ( 67 )] and anti-tumor vaccines [reviewed by Rolih et al ( 68 )]. As CSPG4 displays low expression levels on healthy adult (human and canine) cells and is expressed on the cell surface (Class 1 oncoantigen), it is an ideal target for effective anti-cancer immunotherapy in dogs and humans.…”

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

“…Another interesting approach involves an anti-CSPG4 scFv conjugated to the TNF-related apoptosis-inducing ligand (TRAIL), a soluble protein ligand able to induce apoptosis through binding the cell surface-anchored TRAIL receptor. In a study investigating a TRAIL-fused anti-CSPG4 scFv (based on the mAb 9.2.27), the novel therapeutic candidate showed potent in vitro activity against melanoma cell lines, but no off-target effects on normal melanocytes ( 113 , 114 ). Moreover, it restricted the growth of a human melanoma xenograft in athymic mice.…”

The Significance of Chondroitin Sulfate Proteoglycan 4 (CSPG4) in Human Gliomas

“…Due to the almost exclusive expression from tumor cells, NG2/CSPG4 is an attractive candidate for antibody-based approaches, including specific anti-NG2/CSPG4 antibodies and immuno-based therapies, in particular, for CAR-T immunotherapy of solid tumors [ 29 , 115 , 116 ]. Anti-NG2/CSPG4 mAbs have been shown to inhibit tumor progression by blocking ligand access to the NG2/CSPG4 extracellular binding sites.…”

“…Anti-NG2/CSPG4 mAbs have been shown to inhibit tumor progression by blocking ligand access to the NG2/CSPG4 extracellular binding sites. Therefore, NG2/CSPG4-directed antibody conjugates get selectively internalized by NG2/CSPG4-expressing tumor cells by endocytosis [ 116 ]. Due to selective NG2/CSPG4 upregulation from tumor-associated pericytes, this approach may also contribute to tumor regression via inhibition of neoangiogenesis [ 117 , 118 ].…”