Application of Molecular Mimicry to Target GD2 Ganglioside

Horwacik, Irena; Rokita, Hanna

doi:10.5772/30020

Cited by 2 publications

(2 citation statements)

References 52 publications

(52 reference statements)

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“…The idea of a peptide vaccine eliciting anticarbohydrate response has been precedented in the case of Group B Streptococcus polysaccharide (12). Multiple peptides mimicking GD2 in its binding to specific antibodies were selected using phage display (13,14) and some have been demonstrated to elicit protective, GD2 directed response in preclinical studies. However, the structural basis of peptide-ganglioside mimicry and its relation to the potential of particular peptides to induce GD2 directed immune response remain unknown.…”

Section: Monoclonal Antibodies Targeting Gd2 Ganglioside (Gd2)mentioning

confidence: 99%

Structural Basis of GD2 Ganglioside and Mimetic Peptide Recognition by 14G2a Antibody

Horwacik

Golik

Grudnik

et al. 2015

Molecular & Cellular Proteomics

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Monoclonal antibodies targeting GD2 ganglioside (GD2)have recently been approved for the treatment of high risk neuroblastoma and are extensively evaluated in clinics in other indications. This study illustrates how a therapeutic antibody distinguishes between different types of gangliosides present on normal and cancer cells and informs how synthetic peptides can imitate ganglioside in its binding to the antibody. Using high resolution crystal structures we demonstrate that the ganglioside recognition by a model antibody (14G2a) is based primarily on an extended network of direct and water molecule mediated hydrogen bonds. Comparison of the GD2-Fab structure with that of a ligand free antibody reveals an induced fit mechanism of ligand binding. These conclusions are validated by directed mutagenesis and allowed structure guided generation of antibody variant with improved affinity toward GD2. Contrary to the carbohydrate, both evaluated mimetic peptides utilize a "key and lock" interaction mechanism complementing the surface of the antibody binding groove exactly as found in the empty structure. The interaction of both peptides with the Fab relies considerably on hydrophobic contacts however, the detailed connections differ significantly between the peptides. As such, the evaluated peptide carbohydrate mimicry is defined primarily in a functional and not in structural manner. Molecular & Cellular

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Section: Monoclonal Antibodies Targeting Gd2 Ganglioside (Gd2)mentioning

confidence: 99%

Structural Basis of GD2 Ganglioside and Mimetic Peptide Recognition by 14G2a Antibody

Horwacik

Golik

Grudnik

et al. 2015

Molecular & Cellular Proteomics

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“…Also, generation of anti-idiotype network after administration of mouse 3F8 anti-GD2 monoclonal antibody (mAb) was correlated with outcome of neuroblastoma patients [34]. Other approaches include application of ganglioside and KLH conjugates, anti-ganglioside anti-idiotypic vaccinations that are being tested in clinics, while peptide mimics of GD2 ganglioside and a chimeric antigen receptor (CAR) molecules to target GD2 are currently being developed in preclinical models [35][36][37][38].…”

Section: Gangliosides Are Tumor-associated Antigensmentioning

confidence: 98%

Targeting of tumor-associated gangliosides with antibodies affects signaling pathways and leads to cell death including apoptosis

Horwacik

Rokita

2015

Apoptosis

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Gangliosides are a diverse group of sialic acid containing glycosphigolipids that are abundantly present in an outer plasma membrane of some cells. Biological roles of gangliosides and other lipids in cell fate regulation are being extensively studied. Gangliosides are well known to be involved in interactions between cells and in signal transduction to regulate growth, adhesion and motility. Moreover, many gangliosides are tumor-associated antigens over-expressed on several tumor types. As a result, monoclonal antibodies binding gangliosides can be used to diagnose, monitor and to treat cancer patients. In the review, we gather and discuss data of various research groups on direct cytotoxic effects elicited by several ganglioside-specific antibodies, which bind to GM2, N-acetyl-GM2, N-glycolyl-GM2, GM3, GD3, GD2, O-acetyl-GD2, without involvement of immunological mechanisms. Thus, in cultures of numerous human and mouse cancer cell lines, the antibodies were reported to cause morphological changes, aggregation and detachment of cells, inhibition of proliferation and cell death involving necrosis, apoptosis and oncosis-like mechanisms. Additionally, data on proteome alterations were reviewed that encompass, among others, changes in kinome (P38, JNK, c-MET, ERK1/2, PI3K, AKT, FAK, aurora A, B, C), protein levels of transcription factors (P53, MYCN, HSF1) and pro-apoptotic proteins (caspase 3, BAX). Next, we collected data on application of the antibodies to enhance cytotoxicity of chemotherapeutic drugs and small molecule inhibitors. Finally, further research perspectives on the topic are discussed.

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Application of Molecular Mimicry to Target GD2 Ganglioside

Cited by 2 publications

References 52 publications

Structural Basis of GD2 Ganglioside and Mimetic Peptide Recognition by 14G2a Antibody

Structural Basis of GD2 Ganglioside and Mimetic Peptide Recognition by 14G2a Antibody

Targeting of tumor-associated gangliosides with antibodies affects signaling pathways and leads to cell death including apoptosis

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