Nanoparticle-aided glycovariant assays to bridge biomarker performance and ctDNA results
Sundfeldt K; Terävä J; Kekki H; Pettersson K; Gidwani K; Soukka T
https://urn.fi/URN:NBN:fi-fe2021042820797
Tiivistelmä
Abstract
Numerous immunoassay based cancer
biomarkers established in the 1970 and 1980'ies are widely used in
clinical routine. Initial expectations of biomarkers such as CEA, CA125,
CA19-9, AFP to provide decisive help in the diagnosis of early stage,
pre-symptomatic cancers have not been realized. Thus, they are primarily
used for monitoring disease progression and occasionally being useful
as prognostic indicators. This limitation is due to the marker also
being measurable in healthy individuals and frequently at elevated
concentrations in common benign conditions. Most conventional tumor
markers are glycosylated and interestingly specific alterations of the
glycostructure part can often be seen early in the cancerous process.
Conventional double monoclonal immunoassays are however blind to such
changes as they are based on peptide epitope recognition. Wide
selections of carbohydrate recognizing macromolecules, lectins, but also
glycan structure recognizing antibodies are potentially useful for
detecting such changes. Despite numerous attempts generating
proof-of-principle evidence for this, such assays have generally not
been successfully introduced into clinical routine. The affinity
constants of lectin and glycan specific antibodies for their
corresponding carbohydrate structures may be up to several orders too
low to provide the detection limits and robustness expected from routine
tumor markers. In this review, we describe an approach based on the use
of highly fluorescent Eu3+--chelate dyed nanoparticles onto
which lectins or glycan specific antibodies are coated to provide the
necessary binding strength and signal amplification to provide low
detection limits, while maintaining the original glycan-structure
specificity. This concept applied to three markers, PSA, CA125 and
CA15-3 provide glycoform assays of greatly enhanced cancer specificity
using sample volumes similar or lower than corresponding traditional
ELISAs. For ovarian cancer, we show that this new approach when applied
to ovarian cyst fluid samples provide results similar to the performance
obtained with ctDNA determinations of a set of 17 driver mutations and
greatly superior compared to corresponding conventional immunoassays.
Based on our results, we predict that the nanoparticle-lectin concept
will enable a new generation of simple, low-cost biomarker assays of
highly improved cancer specificity. Such tools should ideally be
evaluated together with determination of ctDNA to establish early
detection schemes for cancers e.g. ovarian, pancreas, lung where the
detection rate of early stage disease is presently unacceptably low.
Kokoelmat
- Rinnakkaistallenteet [19207]