Insights into the immunogenetic basis of two ganglioside-associated idiotypic networks

Rodríguez, Mabel; Roque-Navarro, Lourdes; López‐Requena, Alejandro; Moreno, Ernesto; Acosta, Cristina Mateo de; Pérez, Rolando; Vázquez, Ana María

doi:10.1016/j.imbio.2006.08.005

Cited by 17 publications

(15 citation statements)

References 55 publications

(80 reference statements)

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“…It has been suggested that positive charges at H-CDR3 segment of VH4-34 derived mAbs correlate with oncosis-like cell death mechanisms elicited by these antibodies (45). Interestedly, it was found a motif RXRR in the H-CDR3 of 14F7 mAb (23). Modeling studies together with the crystal structure of 14F7 mAb supported the importance of R98 and R100a in the recognition of NGcGM3 oligosaccharide by this antibody (46).…”

Section: Discussionmentioning

confidence: 85%

“…P3 mAb is restricted to the N-glycolyl sialic acid residue (48), whereas the epitope recognized by 14F7 mAb involved the disaccharide N-glycolyl sialic acid-galactose (46). Also, P3 mAb was encoded by a germ-line VH region (47), whereas 14F7 variable regions were heavily mutated (23), arguing an affinity maturation process. In fact, chimeric 14F7 antibody seemed to have a higher affinity for NGcGM3 than chimeric P3 antibody.…”

Section: Discussionmentioning

confidence: 99%

“…Briefly, 14F7 mAb variable heavy and light chains were amplified by PCR using the corresponding oligonucleotides (23) and cloned into pAH4604 and pAG4622 expression vectors containing human IgG1 and n constant domains, respectively (24). Non-antibodyproducing murine myeloma cell line (NSO) was transfected by electroporation and positive clones were selected using L-histidinol at 10 mmol/L.…”

Section: Methodsmentioning

confidence: 99%

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Anti-ganglioside antibody-induced tumor cell death by loss of membrane integrity

Roque-Navarro

Chakrabandhu

León

et al. 2008

Molecular Cancer Therapeutics

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Gangliosides have been involved in multiple cellular processes such as growth, differentiation and adhesion, and more recently as regulators of cell death signaling pathways. Some of these molecules can be considered as tumor-associated antigens, in particular, N-glycolyl sialic acid -containing gangliosides, which are promising candidates for cancer-targeted therapy because of their low expression in normal human tissues. In this study, we provided the molecular and cellular characterization of a novel cell death mechanism induced by the anti-NGcGM3 14F7 monoclonal antibody (mAb) in L1210 murine tumor cell line but not in mouse normal cells (B and CD4 + T lymphocytes) that expressed the antigen. Impairment of ganglioside synthesis in tumor cells abrogated the 14F7 mAb cytotoxic effect; however, exogenous reincorporation of the ganglioside did not restore tumor cell sensitivity to 14F7 mAb-induced cytotoxicity. 14F7 F(ab ¶) 2 but not Fab fragments retained the cytotoxic capacity of the whole mAb. By contrary, other mAb, which recognizes N-glycolylated gangliosides, did not show any cytotoxic effect. These mAbs showed quite different capacities to bind NGcGM3-positive cell lines measured by binding inhibition experiments. Interestingly, this complementindependent cell death mechanism did not resemble apoptosis, because no DNA fragmentation, caspase activation, or Fas mediation were observed. However, NGcGM3 ganglioside-mediated 14F7 mAb-induced cell death was accompanied by cellular swelling, membrane lesion formation, and cytoskeleton activation, suggesting an oncosislike phenomenon. This novel mechanism of cell death lets us to support further therapeutic approaches using NGcGM3 as a molecular target for antibody-based cancer immunotherapy.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Anti-ganglioside antibody-induced tumor cell death by loss of membrane integrity

Roque-Navarro

Chakrabandhu

León

et al. 2008

Molecular Cancer Therapeutics

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“…Pérez et al (23) showed that lymph node cells from BALB/c mice immunized with P3 mAb proliferated in vitro, in a dose-dependent manner, not only in response to P3 mAb but also to 1E10 mAb, suggesting the existence of a naturally occurring B-T cell idotypic network. Rodríguez et al (48) showed that chickens immunized with P3 mAb (Ab1) or 14F7 mAb (Ab1), another Ab specific for NeuGcGM3, developed an anti-idiotypic response against both immunizing Abs. Only those chickens, however, immunized with P3 mAb were able to develop a strong and specific Ab response against N-glycosylated gangliosides.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Antibody Response against NeuGcGM3 Ganglioside Elicited in Non-Small Cell Lung Cancer Patients Immunized with an Anti-Idiotype Antibody

Hernández¹,

Toledo²,

Martínez³

et al. 2008

The Journal of Immunology

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1E10 mAb is an anti-Id murine mAb (Ab2 mAb) specific for an Ab1 mAb that reacts with NeuGc-containing gangliosides, sulfatides, and Ags expressed in some human tumors. In preclinical studies, this Ab2 Ab was able to mimic NeuGc-containing gangliosides only in animals lacking expression of these Ags in normal tissues. In this study, we report on the immune responses elicited in 20 non-small cell lung cancer patients treated with 1 mg of aluminum hydroxide-precipitated 1E10 mAb. In the hyperimmune sera from 16 of 20 patients, a strong specific Ab response of both IgM and IgG isotypes against NeuGcGM3 ganglioside was observed. Patient immune sera were able to induce complement-independent cell death of NeuGcGM3-expressing X63 murine myeloma target cells. Significant immunoreactivity to NeuGcGM3 was still detected after the complete abrogation of the reactivity against 1E10 mAb by the adsorption of patient sera with this Ab. We hypothesize that Id−Ag+ Abs could reflect the activation of an autologous idiotypic cascade into the patients. Both Id+Ag+ and Id−Ag+ fractions were separated by affinity chromatography and characterized. Although IgG isotype Abs were found in both fractions, IgM isotype Abs were found only in the Id−Ag+ fraction. Both Id+Ag+ and Id−Ag+ Abs were able to specifically recognize and induce cell death in NeuGcGM3-expressing X63 myeloma target cells. Patients that developed IgG and/or IgM Abs against NeuGcGM3 showed longer median survival times.

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“…Evidences of an affinity maturation process were found in 14F7 mAb variable region. 79 P3 is ©2 0 1 1 L a n d e s B i o s c i e n c e .…”

confidence: 99%

Lonely killers

Fernández-Marrero

López‐Requena²

2011

mAbs

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Insights into the immunogenetic basis of two ganglioside-associated idiotypic networks

Cited by 17 publications

References 55 publications

Anti-ganglioside antibody-induced tumor cell death by loss of membrane integrity

Anti-ganglioside antibody-induced tumor cell death by loss of membrane integrity

Characterization of the Antibody Response against NeuGcGM3 Ganglioside Elicited in Non-Small Cell Lung Cancer Patients Immunized with an Anti-Idiotype Antibody

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