Vaccination with anti-idiotype antibody ganglidiomab mediates a GD2-specific anti-neuroblastoma immune response

Lode, Holger N.; Schmidt, Manuela; Seidel, Daniel; Huebener, Nicole; Brackrock, Diana; Bleeke, Matthias; Reker, Daniel; Brandt, Sven Van; Mueller, Hans-Peter; Helm, Christiane A.; Siebert, Nikolai

doi:10.1007/s00262-013-1413-y

Cited by 48 publications

(64 citation statements)

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“…Ganglidiomab anti-idiotype (anti-Id) Ab was isolated from hybridoma cells as previously described [17]. Briefly, the concentration of ganglidiomab in hybridoma supernatants was determined by ELISA using ch14.18/CHO as a capture mAb [17].…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, the concentration of ganglidiomab in hybridoma supernatants was determined by ELISA using ch14.18/CHO as a capture mAb [17]. Hybridoma supernatants containing 50 µg/ml of ganglidiomab were filtered and ganglidiomab was concentrated followed by binding to protein G as previously described.…”

Section: Methodsmentioning

confidence: 99%

“…Hybridoma supernatants containing 50 µg/ml of ganglidiomab were filtered and ganglidiomab was concentrated followed by binding to protein G as previously described. After wash steps ganglidiomab was eluted and quantified with ELISA using ch14.18/CHO as a capture mAb [17]. The final product contained 500 µg/ml of ganglidiomab and was used for further assay developments.…”

Section: Methodsmentioning

confidence: 99%

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Functional Bioassays for Immune Monitoring of High-Risk Neuroblastoma Patients Treated with ch14.18/CHO Anti-GD2 Antibody

et al. 2014

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Effective treatment of high-risk neuroblastoma (NB) remains a major challenge in pediatric oncology. Human/mouse chimeric monoclonal anti-GD2 antibody (mAb) ch14.18 is emerging as a treatment option to improve outcome. After establishing a production process in Chinese hamster ovary (CHO) cells, ch14.18/CHO was made available in Europe for clinical trials. Here, we describe validated functional bioassays for the purpose of immune monitoring of these trials and demonstrate GD2-specific immune effector functions of ch14.18/CHO in treated patients. Two calcein-based bioassays for complement-dependent- (CDC) and antibody-dependent cellular cytotoxicity (ADCC) were set up based on patient serum and immune cells tested against NB cells. For this purpose, we identified LA-N-1 NB cells as best suited within a panel of cell lines. Assay conditions were first established using serum and cells of healthy donors. We found an effector-to-target (E:T) cell ratio of 20∶1 for PBMC preparations as best suited for GD2-specific ADCC analysis. A simplified method of effector cell preparation by lysis of erythrocytes was evaluated revealing equivalent results at an E:T ratio of 40∶1. Optimal results for CDC were found with a serum dilution at 1∶8. For validation, both within-assay and inter-assay precision were determined and coefficients of variation (CV) were below 20%. Sample quality following storage at room temperature (RT) showed that sodium-heparin-anticoagulated blood and serum are stable for 48 h and 96 h, respectively. Application of these bioassays to blood samples of three selected high-risk NB patients treated with ch14.18/CHO (100 mg/m2) revealed GD2-specific increases in CDC (4.5–9.4 fold) and ADCC (4.6–6.0 fold) on day 8 compared to baseline, indicating assay applicability for the monitoring of multicenter clinical trials requiring sample shipment at RT for central lab analysis.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Functional Bioassays for Immune Monitoring of High-Risk Neuroblastoma Patients Treated with ch14.18/CHO Anti-GD2 Antibody

et al. 2014

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“…Over several years, different strategies aimed at promoting anti-ganglioside immune responses have been studied, with disparate success. Besides the direct vaccination with GSL conjugated to adjuvants such as keyhole limpet haemocyanin [142], other approaches like anti-idiotypic antibodies [143], chimeric T cells [144], genetically-engineered antibodies [145] and GSL-mimicking peptides [146] have been assayed. These various strategies have been extensively reviewed elsewere [147,148].…”

Section: Discussionmentioning

confidence: 99%

Immune Response Modulation by Tumor-Secreted Glycosphingolipids

Lardone¹,

Cely²,

Sieling³

et al. 2015

J Glycobiol

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Although originally considered merely structural components of cellular membranes, glycosphingolipids (GSL) are now recognized as having critical effects on cellular physiology, including proliferation, differentiation, viral transformation and ontogenesis. In addition, a vast majority of human cancers have modified GSL composition compared to parental normal cells. These modifications may contribute to both tumor survival and exert striking effects on anti-tumor immunity. In this review, we discuss mechanisms of immune modulation by tumor-secreted GSL.

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“…In one study, ganglidiomab was generated following immunization of Balb/c mice with 14G2a and splenocytes were then harvested to generate hybridoma cells. It was demonstrated induction of a GD2-specific humoral immune response after vaccination of mice with ganglidiomab effective in mediating GD2-specific killing of neuroblastoma cells (100). In other investigations, the murine monoclonal anti-ganglioside GD2 antibody 14.G2a was used to generate the monoclonal anti-idiotype 1A7 (85) which has been used as an anti-idiotype vaccine in patients with advanced melanoma (87, 88).…”

Section: Immunotherapies Using Ganglioside Gd2 As the Targetmentioning

confidence: 99%

Glycosylation of Glycolipids in Cancer: Basis for Development of Novel Therapeutic Approaches

et al. 2013

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Altered networks of gene regulation underlie many pathologies, including cancer. There are several proteins in cancer cells that are turned either on or off, which dramatically alters the metabolism and the overall activity of the cell, with the complex machinery of enzymes involved in the metabolism of glycolipids not being an exception. The aberrant glycosylation of glycolipids on the surface of the majority of cancer cells, associated with increasing evidence about the functional role of these molecules in a number of cellular physiological pathways, has received considerable attention as a convenient immunotherapeutic target for cancer treatment. This has resulted in the development of a substantial number of passive and active immunotherapies, which have shown promising results in clinical trials. More recently, antibodies to glycolipids have also emerged as an attractive tool for the targeted delivery of cytotoxic agents, thereby providing a rationale for future therapeutic interventions in cancer. This review first summarizes the cellular and molecular bases involved in the metabolic pathway and expression of glycolipids, both in normal and tumor cells, paying particular attention to sialosylated glycolipids (gangliosides). The current strategies in the battle against cancer in which glycolipids are key players are then described.

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Vaccination with anti-idiotype antibody ganglidiomab mediates a GD2-specific anti-neuroblastoma immune response

Abstract: We generated and characterized a novel anti-idiotype antibody ganglidiomab and demonstrated activity against neuroblastoma.

Cited by 48 publications

References 20 publications

Functional Bioassays for Immune Monitoring of High-Risk Neuroblastoma Patients Treated with ch14.18/CHO Anti-GD2 Antibody

Functional Bioassays for Immune Monitoring of High-Risk Neuroblastoma Patients Treated with ch14.18/CHO Anti-GD2 Antibody

Immune Response Modulation by Tumor-Secreted Glycosphingolipids

Glycosylation of Glycolipids in Cancer: Basis for Development of Novel Therapeutic Approaches

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