Genetically engineered humanized anti‐ganglioside GM2 antibody against multiple organ metastasis produced by GM2‐expressing small‐cell lung cancer cells

Yamada, Tadaaki; Bando, Hideaki; Takeuchi, Shinji; Kita, Kenji; Li, Qi; Wang, Wei; Akinaga, Shiro; Nishioka, Yasuhiko; Sone, Saburo; Yano, Seiji

doi:10.1111/j.1349-7006.2011.02093.x

Cited by 35 publications

(28 citation statements)

References 23 publications

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“…Some tumor cells have altered ganglioside expression compared with untransformed cells, and some overexpress GM2 [56]–[58]. Humanized antibodies directed against GM2 prevent the formation of organ metastases in mice with small-cell lung cancer [59]. It is possible that ganglioside overexpression in tumor cells alters the susceptibility of certain cancers to reovirus infection.…”

Section: Discussionmentioning

confidence: 99%

The GM2 Glycan Serves as a Functional Coreceptor for Serotype 1 Reovirus

et al. 2012

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Viral attachment to target cells is the first step in infection and also serves as a determinant of tropism. Like many viruses, mammalian reoviruses bind with low affinity to cell-surface carbohydrate receptors to initiate the infectious process. Reoviruses disseminate with serotype-specific tropism in the host, which may be explained by differential glycan utilization. Although α2,3-linked sialylated oligosaccharides serve as carbohydrate receptors for type 3 reoviruses, neither a specific glycan bound by any reovirus serotype nor the function of glycan binding in type 1 reovirus infection was known. We have identified the oligosaccharide portion of ganglioside GM2 (the GM2 glycan) as a receptor for the attachment protein σ1 of reovirus strain type 1 Lang (T1L) using glycan array screening. The interaction of T1L σ1 with GM2 in solution was confirmed using NMR spectroscopy. We established that GM2 glycan engagement is required for optimal infection of mouse embryonic fibroblasts (MEFs) by T1L. Preincubation with GM2 specifically inhibited type 1 but not type 3 reovirus infection of MEFs. To provide a structural basis for these observations, we defined the mode of receptor recognition by determining the crystal structure of T1L σ1 in complex with the GM2 glycan. GM2 binds in a shallow groove in the globular head domain of T1L σ1. Both terminal sugar moieties of the GM2 glycan, N-acetylneuraminic acid and N-acetylgalactosamine, form contacts with the protein, providing an explanation for the observed specificity for GM2. Viruses with mutations in the glycan-binding domain display diminished hemagglutination capacity, a property dependent on glycan binding, and reduced capacity to infect MEFs. Our results define a novel mode of virus-glycan engagement and provide a mechanistic explanation for the serotype-dependent differences in glycan utilization by reovirus.

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Section: Discussionmentioning

confidence: 99%

The GM2 Glycan Serves as a Functional Coreceptor for Serotype 1 Reovirus

et al. 2012

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“…Moreover, a recent study by Yamada et al provides important evidence supporting both the role of sphingolipids in lung cancer growth and metastasis and the potential for effective therapeutic intervention by targeting sphingolipids. Their study showed high expression of the glycosphingolipid ganglioside GM2 (monosialic ganglioside 2) in small-cell lung cancer (SCLC) human specimens and, using an in vivo tumor xenograft mouse model, demonstrated that an anti-GM2 antibody-based therapy could block SCLC metastases and increase cancer cell apoptosis, thereby prolonging the mouse' survival (Yamada et al 2011). However, as of yet, there are no molecular mechanisms explaining this observation.…”

Section: Sphingolipids In Lung Cancer: a Field That Needs Research mentioning

confidence: 99%

Lung Cancer and Lung Injury: The Dual Role of Ceramide

Goldkorn

Chung

Filosto

2013

Handbook of Experimental Pharmacology

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Sphingolipids play key roles in cancer, yet our current understanding of sphingolipid function in lung cancer is limited to a few key players. The best characterized of these are sphingosine-1-phoshate and ceramide which are described for their opposing roles in cell fate. However, because sphingolipids as a whole are readily interconverted by a complex enzymatic machinery, no single sphingolipid appears to have exactly one role. Instead, the roles of specific sphingolipids appear to be context specific as demonstrated by findings that ceramide-1-phosphate has both proliferative and apoptotic effects depending on its concentration. Therefore, we present herein several years of research on ceramide, a sphingolipid linked to apoptotic signaling, that is emerging in cancer research for its potential roles in proliferation and cell-to-cell communication via exosomes. Ceramide is a well-studied sphingolipid in both normal and pathological conditions ranging from skin development to lung cancer. Interestingly, several groups have previously reported its increased levels in emphysema patients who are smokers, a patient subpopulation greatly susceptible to lung cancer. However, the molecular mechanisms through which cigarette smoke (CS) and ceramide accumulation lead to lung cancer, non-small cell lung cancer (NSCLC) specifically, are unknown. Interestingly, recent studies clearly establish that two signaling pathways are activated during CS exposure in the lung airway. One centers on the activation of neutral sphingomyelinase2 (nSMase2), an enzyme that hydrolyzes sphingomyelin to ceramide. The other pathway focuses on the oncogenic EGF receptor (EGFR), which becomes aberrantly activated but not degraded, leading to prolonged proliferative signaling. Recent studies show that these two signaling pathways may actually converge and integrate. Specifically, Goldkorn et al. demonstrated that during CS exposure, EGFR is favorably co-localized in ceramide-enriched regions of the plasma membrane, proposing that nSMase2/ceramide plays a role in the aberrant EGFR activation, leading to augmented tumorigenic signaling. Moreover, new findings indicate that CS exposure may induce resistance to the tyrosine kinase inhibitors (TKIs), used for treatment of NSCLC, merely through posttranslational molecular alterations. Furthermore, structural anomalies of the CS-activated EGFR appear to be supported by the excess ceramide produced by the CS-activated nSMase2 in the plasma membrane of lung epithelial cells. We present in this chapter the progression of the sphingolipid field in lung cancer using ceramide as an example. However, many crucial questions remain to be answered regarding the role of sphingolipids in lung cancer because of the glut of promising observations.

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“…ADCC has been described as one of the effector mechanisms associated with antibodies against tumor-associated gangliosides (Chapman et al, 1990;Fukumoto et al, 1999;Terme et al, 2014;Yamada et al, 2011). It was previously reported that high concentrations of mouse 14F7 mAb were required to induce ADCC in GM3(Neu5Gc)-expressing P3 × 63 cells.…”

Section: Discussionmentioning

confidence: 95%