CD22 is a cell-surface glycoprotein uniquely located on mature B-cells and
B-cell derived tumour cells. Current evidence suggests that binding of endo
genous ligands to CD22 leads to modulation of B-cell activation by antigen.
Incidentally, however, B-cell activation may derail, and lead to an undesi
red immune response, for example in cases of allergy, rheumatoid arthritis
and Crohn's disease. In this situation, synthetic high-affinity ligands for
CD22 may be of therapeutic value as inhibitors of B-cell activation. Recen
t studies have revealed that natural ligands for CD22 contain the trisaccha
ride NeuAc alpha -2,6-Lac as the basic binding motif. In addition, it has b
een demonstrated that binding to CD22 is strongly enhanced by multivalent p
resentation of the basic binding motif (cluster effect). In this paper, the
stepwise development of a novel multivalent high-affinity ligand for CD22
is described. In the first stage, a series of monovalent NeuAc alpha -2,6-G
lc(Y)X type binding motifs was prepared, and their affinity for murine CD22
was monitored, to obtain more insight into the effect of separate structur
e elements on ligand recognition. In the second stage, we prepared a trival
ent cluster, based on the monovalent motif that displayed the highest affin
ity for CD22, NeuAccc2,6-GlcNBzNO(2)OMe (7). This cluster, TRIS(NeuAc alpha
-2,6-GlcNBzNO(2))(3) (52), displayed a more than 58-fold higher affinity f
or CD22 than the reference structure NeuAc alpha -2,6-LacOMe (10). To our k
nowledge, the cluster 52 is one of the most potent antagonists for CD22, ye
t synthesised. (C) 2000 Elsevier Science Ltd. All rights reserved.