Glycopeptide probes detect tumor-associated antibodies in blood samples
Pancreatic cancer is one of the most lethal forms of
cancer, primarily because it is usually diagnosed very late. Current
markers are too insensitive and unspecific for early detection
screenings. In the journal Angewandte Chemie, a research team has
now introduced a new method that could lead to a significantly more
precise and reliable diagnosis. It is based on the selective detection
of specific antibodies in blood samples.
© Wiley-VCH, re-use with credit to 'Angewandte Chemie' and a link to the original article.
Tumors produce certain proteins (tumor-associated antigens)
that draw the attention of our constantly “patrolling” immune system and
trigger an immune response. As a consequence, antibodies directed
against the tumors (tumor-associated autoantibodies) are formed,
circulating in the blood at very early stages of the disease—which makes
them useful for early detection. An international team led by Roberto
Fiammengo and Giovanni Malerba at the University of Verona (Italy) as
well as Alfredo Martínez at the Center for Biomedical Research of La
Rioja (Logroño, Spain) and Francisco Corzana at the Universidad de La
Rioja , has now developed an approach to diagnostic testing for
pancreatic cancer that is based on the detection of such special
tumor-associated autoantibodies.
They chose to use autoantibodies directed against the
tumor-associated form of mucin-1 (TA-MUC1). Mucin-1 is a heavily
glycosylated protein (a protein with sugar components) that occurs, for
example, in glandular tissue. In many types of tumors, including
pancreatic cancer, it is found in significantly elevated concentrations.
In addition, the pattern of glycosylation is different from the normal
form. The team’s goal was to detect autoantibodies that are directed
specifically against TA-MUC1 and are a clear indicator of pancreatic
cancer.
Based on structural analyses and computer simulations of
known antibodies against TA-MUC1 (SM3 and 5E5), the team designed a
collection of synthetic glycopeptides that mimic different segments
(epitopes) of TA-MUC1. They also made unnatural modifications to
increase the chances of identifying autoantibody subgroups indicative of
the disease. The team immobilized these model antigens on gold
nanoparticles achieving probes suitable for a serological assay
(dot-blot assay). The diagnostic assay was validated with real samples
from patients with pancreatic cancer and a healthy control group. Some
of the nanoparticle probes could differentiate very well between samples
from diseased and healthy individuals demonstrating they detected tumor
associated autoantibodies. Notably, these specific autoantibodies
displayed significantly better correct positive/false positive ratios
than current clinical biomarkers for pancreatic cancer.
Probes with smaller glycopeptide antigens that correspond
to only a single epitope, gave better results than larger probes that
mimic multiple epitopes—an advantage for easier synthetic production. A
short glycopeptide with an unnatural modification to its sugar component
was found to be particularly effective for the detection of
discriminating autoantibodies. This new structure-based approach could
help in the selection of autoantibody subgroups with higher tumor
specificity.
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About the Author
Dr.Roberto Fiammengo is an Associate Professor at the
University of Verona (Italy). His main expertise is the development of
biofunctionalized nanomaterials for biomedical and diagnostic
applications. Dr. Francisco Corzana is Professor at the University of La
Rioja (Spain). He is an expert on the synthesis and conformational
analysis of O-glycopeptides in solution and bound to antibodies or
lectins. Dr. Fiammengo and Dr. Corzana share a common interest in
understanding the response of the immune system towards glycosylated
tumor antigens.
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