Antibody recognition of aberrant glycosylation on the surface of cancer cells

Soliman, Caroline; Yuriev, Elizabeth; Ramsland, Paul A.

doi:10.1016/j.sbi.2016.10.009

Cited by 32 publications

(30 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One intriguing aspect of the small NeuGc GM3 glycan head group is that it would bring the scFv in close proximity to the plasma membrane, thus logically implying a potential interaction with lipids surrounding the ganglioside. In fact, molecular dynamics simulations have suggested that GM3 is deeply embedded in the cell membrane and that only the terminal saccharides are exposed 49 , 50 . Moreover, the interaction of gangliosides with cholesterol in lipid rafts appears to bend the glycolipid head group into a conformation almost parallel to the membrane 51 , 52 .…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of an L chain optimised 14F7 anti-ganglioside Fv suggests a unique tumour-specificity through an unusual H-chain CDR3 architecture

Bjerregaard-Andersen

Johannesen

Abdel-Rahman

et al. 2018

Sci Rep

View full text Add to dashboard Cite

Targeted cancer immunotherapy offers increased efficacy concomitantly with reduced side effects. One antibody with promising clinical potential is 14F7, which specifically recognises the NeuGc GM3 ganglioside. This antigen is found in the plasma membrane of a range of tumours, but is essentially absent from healthy human cells. 14F7 can discriminate NeuGc GM3 from the very similar NeuAc GM3, a common component of cell membranes. The molecular basis for this unique specificity is poorly understood. Here we designed and expressed 14F7-derived single-chain Fvs (scFvs), which retained the specificity of the parent antibody. Detailed expression and purification protocols are described as well as the synthesis of the NeuGc GM3 trisaccharide. The most successful scFv construct, which comprises an alternative variable light chain (VLA), allowed structure determination to 2.2 Å resolution. The structure gives insights into the conformation of the important CDR H3 loop and the suspected antigen binding site. Furthermore, the presence of VLA instead of the original VL elucidates how this subdomain indirectly stabilises the CDR H3 loop. The current work may serve as a guideline for the efficient production of scFvs for structure determination.

show abstract

Section: Discussionmentioning

confidence: 99%

Crystal structure of an L chain optimised 14F7 anti-ganglioside Fv suggests a unique tumour-specificity through an unusual H-chain CDR3 architecture

Bjerregaard-Andersen

Johannesen

Abdel-Rahman

et al. 2018

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Post-translational modification by glycosylation provides greater diversity than any other modifications of the proteome, and altered protein glycosylation patterns emerge as a new generation of diagnostic biomarkers in cancer [ 36 ]. Further, glycosylation-targeting antibodies are being developed for a broad range of cancers, based on the recognition of glycan epitopes aberrantly expressed in malignant cells [ 37 , 38 ]. In this study, we provide evidence of a role for glycosylation in tumor antigen internalization with potential implications for ADC delivery and cytotoxic activity in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Tumor antigen glycosaminoglycan modification regulates antibody-drug conjugate delivery and cytotoxicity

et al. 2017

View full text Add to dashboard Cite

Aggressive cancers are characterized by hypoxia, which is a key driver of tumor development and treatment resistance. Proteins specifically expressed in the hypoxic tumor microenvironment thus represent interesting candidates for targeted drug delivery strategies. Carbonic anhydrase (CAIX) has been identified as an attractive treatment target as it is highly hypoxia specific and expressed at the cell-surface to promote cancer cell aggressiveness. Here, we find that cancer cell internalization of CAIX is negatively regulated by post-translational modification with chondroitin or heparan sulfate glycosaminoglycan chains. We show that perturbed glycosaminoglycan modification results in increased CAIX endocytosis. We hypothesized that perturbation of CAIX glycosaminoglycan conjugation may provide opportunities for enhanced drug delivery to hypoxic tumor cells. In support of this concept, pharmacological inhibition of glycosaminoglycan biosynthesis with xylosides significantly potentiated the internalization and cytotoxic activity of an antibody-drug conjugate (ADC) targeted at CAIX. Moreover, cells expressing glycosaminoglycan-deficient CAIX were significantly more sensitive to ADC treatment as compared with cells expressing wild-type CAIX. We find that inhibition of CAIX endocytosis is associated with an increased localization of glycosaminoglycan-conjugated CAIX in membrane lipid raft domains stabilized by caveolin-1 clusters. The association of CAIX with caveolin-1 was partially attenuated by acidosis, i.e. another important feature of malignant tumors. Accordingly, we found increased internalization of CAIX at acidic conditions. These findings provide first evidence that intracellular drug delivery at pathophysiological conditions of malignant tumors can be attenuated by tumor antigen glycosaminoglycan modification, which is of conceptual importance in the future development of targeted cancer treatments.

show abstract

“…Dominant was the reduced or lost specificity for Gala-or GalNAc-terminated glycan epitopes in PAD patients, to which healthy individuals express high levels of naturally occurring antibodies, eventually in response to immune stimulation by carbohydrate antigens of their microbiota. 9,41 Thus, the loss of Gala-or GalNAc-specific antibodies might reflect the lost capacity to induce these antibodies in response to the host microbiota, the microbial dysbiosis in PAD, 4 or both. Interestingly, bacteria and tumor cells use certain glycosylation patterns to escape immunity, such as sialoglycans that engage inhibitory Siglec receptors on leukocyte subsets of myeloid and lymphoid lineages.…”

Section: Discussionmentioning

confidence: 99%

The architecture of the IgG anti-carbohydrate repertoire in primary antibody deficiencies

Jandus

Boligan

Smith

et al. 2019

Blood

View full text Add to dashboard Cite

show abstract

Antibody recognition of aberrant glycosylation on the surface of cancer cells

Cited by 32 publications

References 46 publications

Crystal structure of an L chain optimised 14F7 anti-ganglioside Fv suggests a unique tumour-specificity through an unusual H-chain CDR3 architecture

Crystal structure of an L chain optimised 14F7 anti-ganglioside Fv suggests a unique tumour-specificity through an unusual H-chain CDR3 architecture

Tumor antigen glycosaminoglycan modification regulates antibody-drug conjugate delivery and cytotoxicity

The architecture of the IgG anti-carbohydrate repertoire in primary antibody deficiencies

Contact Info

Product

Resources

About