PMC:3431878 / 12317-16570
Annnotations
{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/3431878","sourcedb":"PMC","sourceid":"3431878","source_url":"https://www.ncbi.nlm.nih.gov/pmc/3431878","text":"4. Antigenic Determinants\nNumerous antibodies have been generated against CA125 since the initial discovery in 1981. These antibodies are classified as OC125-like (group A), M11-like (group B) or OV197 (group C) depending on the antigenic determinant recognized [31]. These antibodies are further subdivided into groups A1–A4 (OC125-like), B1/B2 (M11-like) and C1/C2 (OV197-like) [32,33]. It is important to note that although there are two antibodies classified as OV197-like, the antigenic recognition behavior of OV197 is different to that of 7C12 [32]. Extensive investigation into the epitope recognition of the different class antibodies to CA125 has been performed by the International Society of Oncology and Biomarkers (ISOBM) TD-1 workshop [31]. Cross-inhibition and immunometric assays have been used to examine the various epitopes on CA125 isolated from normal abdominal fluids, cervical mucus, cell culture and ascites [32]. From this the importance of antibody class combinations for accurate detection of CA125 was revealed. Furthermore, differential antibody interaction with CA125 isolated in low-molecular-weight fractions was also highlighted. Here, different immunometric assay combinations resulted in different CA125 activity levels in those fractions [32]. It was noted that the difference in assay results could be due to the different behavior of the antibody combinations towards the low-molecular-weight fractions of CA125 preparations [32]. Conversely, fractions containing high-molecular-weight CA125 yielded similar CA125 activity levels regardless of the antibody pair used in the immune-assay. As high-molecular-weight forms of CA125 are the major component in most samples this phenomenon should, therefore, not interfere with the immunometric assays even if the standards used do not have the same composition as the sample [32].\nOC125-like and M11-like antibodies are proposed to detect a cysteine enclosed loop (C-loop) structure in the repeat domain [18,31,32] with a paucity of glyco-structures in the immediate proximity [18]. Extrapolated from the C-loop of a murine derived CA125 repeat domain homolog, Maeda et al. suggested that this antigenic region forms a β-sheet structure [22]. This was later confirmed with a synthesized 21 amino acid long human CA125 antigenic domain [23]. Here, a serine in position 8 of the loop was found to be essential for structural formation [23]. However, it is important to note that this serine at position 8 is conserved in the repeat sequences, throughout human CA125, in only around 25% of the cases. In approximately 60% of repeat sequences a proline is found at position 8, which results in random coil formation [23].\nThe fourth report from ISOBM TD-1 workshop described the use of a recombinant sequence of the 11th repeat from the N-terminus (R11) to test the binding capacity of various OC125-like, M11-like and OV197-like antibodies [33]. It was shown that the binding of the various monoclonal antibodies differed between the groups and subgroups. Within group A, subgroups A3 and A4 showed high binding to R11. Group B also displayed high reactivity with the exception of four investigated M11-like antibodies that showed low to no binding [33]. Additionally, group C antibodies had shown only little or no reactivity [33]. From those results it was concluded that the poor or absent binding of some antibodies towards R11 is unlikely to be due to a disparate sequence of this particular repeat to the other +60 repeat sequences, as there are only three main epitope families identified to date [33]. This observation was thought to be, more likely, a result of the single R11 repeat not exhibiting an optimal conformation as it is no longer in its native context [33]. This was exemplified by the binding behavior of OC125, which binds poorly to R11 [33] yet shows strong binding to a recombinant 3 tandem repeat form of CA125 [34].\nFurthermore, glycosylation of CA125 has also been shown to be important for high affinity antibody binding. Deglycosylation with PNGase F led to lower affinity binding of the OC125 antibody to CA125 [7]. However, the exact influence glycosylation has on the binding affinity of the different antibody classes to CA125 is 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