Switching on cytotoxicity by a single mutation at the heavy chain variable region of an anti-ganglioside antibody

Yuniel Fernández-Marrero, Tays Hernández, Lourdes Roque-Navarro, Ariel Talavera, Ernesto Moreno, Tania Griñán, Ana María Vázquez, Cristina Mateo de Acosta, Rolando Pérez, Alejandro López-Requena

Producción científica: Contribución a una revistaArtículorevisión exhaustiva

20 Citas (Scopus)

Resumen

Gangliosides are sialic acid-containing glycosphingolipids present in the plasma membrane of most mammalian cells. In humans, the expression of the N-glycolylated (Neu5Gc) variant of the sialic acid has been associated with malignant transformation, constituting therefore an attractive target for cancer immunotherapy. P3 monoclonal antibody (mAb) recognizes Neu5Gc-containing gangliosides, as well as sulfatides. Heavy chain CDR3 (H-CDR3) arginine residues have been shown to be crucial for ganglioside recognition, but less important for anti-idiotypic antibody binding. Here, we describe the effect on antibody reactivity of different mutations involving a single H-CDR3 acid residue. Substitution of glutamate 99 (Kabat numbering) by arginine, aspartate or serine residues resulted in no differences in anti-idiotype binding. However, the first mutation caused increased reactivity with the antigen, including a cytotoxic effect of the antibody on ganglioside-expressing cells previously unseen for the wild type antibody. Another antibody that recognizes N-glycolyl-GM3 ganglioside (GM3(Neu5Gc)), but not other glycolipids, named 14F7, exhibits also an arginine-enriched H-CDR3 and a complement-independent cell death activity. Unlike 14F7 mAb, the cytotoxicity of the P3 E99→R mutant antibody did not exclusively depend on ganglioside expression on tumor cells.

Idioma originalInglés
Páginas (desde-hasta)1059-1067
Número de páginas9
PublicaciónMolecular Immunology
Volumen48
N.º8
DOI
EstadoPublicada - abr. 2011
Publicado de forma externa

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