Activity of MUC1 cancer antigen-binding plasma anti-α-galactoside antibody correlates inversely with size of autologous lipoprotein(a)

Abstract

Variation in ligand-binding affinity of natural plasma anti-α-galactoside antibody (anti-Gal) is a plausible reason for differing anti-cancer defense among individuals since serine- and threonine-rich peptide sequences (STPS) in the cancer-specific MUC-1 antigen are surrogate ligands for this antibody. As affinity of a natural antibody could be modulated by systemic antigens by processes including affinity maturation, we examined the contribution of the size of lipoprotein(a) [Lp(a)], an efficient autologous anti-Gal-binding macromolecule that possesses variable numbers of STPS due to genetically determined size polymorphism, towards the specific activity (activity per unit mass) of anti-Gal. Binding of purified Lp(a) to FITC-labeled anti-Gal, measured in terms of increase in fluorescence of the latter, was inhibited by LDL in proportion to Lp(a) size presumably because LDL molecules also bind noncovalently and in proportion to Lp(a) size at the O-glycosylated and STPS-rich region of Lp(a). For the same reason, circulating forms of smaller Lp(a) which carried fewer or no noncovalently attached LDL molecules were more efficient ligands for the antibody than the same number of larger ones (P < 0.0001). Result suggested that smaller Lp(a), with their STPS ligands less obstructed by adhering LDL, would be more effective systemic antigens for anti-Gal. In confirmation of this, the specific activity of anti-Gal decreased with Lp(a) size (r − 0.5443; P < 0.0001) but increased with Lp(a) concentration (r 0.6202; P < 0.0001) among 73 normal plasma samples. IgG to IgM ratio, an index of immunoglobulin class switching characteristic of affinity maturation, was decidedly higher for anti-Gal in small Lp(a) individuals than in their large Lp(a) counterparts (P = 0.0014). Results indicated that modulation of activity of anti-Gal by Lp(a) size may account for the lower incidence of cancer reported in people carrying more plasma Lp(a) which are generally smaller as well.