EVIDENCE FOR AN UPPER AFFINITY THRESHOLD FOR ANTI-IGM-INDUCED APOPTOSIS IN A HUMAN B-CELL LYMPHOMA

The influence of ligand:receptor affinity on B-cell antigen receptor ( BCR)-induced apoptosis in the IgM(+) Burkitt lymphoma line, Ramos, was evaluated with a group of affinity-diverse murine monoclonal antibodi es (MoAbs) specific for human B-cell IgM. The studies showed not only a minimal affinity threshold for the induction of apoptosis, but, inte restingly, also a maximal affinity threshold above which increases in affinity were associated with diminished apoptosis. The lesser capacit y of high-affinity MoAb to induce apoptosis was paralleled by a lesser capacity to induce receptor cross-linking. At high ligand concentrati on, high MoAb affinity was also associated with a diminished capacity to induce early protein tyrosine phosphorylation. The compromised capa city of two high-affinity MoAbs to trigger apoptosis may be, at least in part, explained by two separate phenomena that can impair the forma tion of mlgM crosslinks: (1) more stable univalent binding and (2) a t endency for monogamous binding of both MoAb Fab to two Fab epitopes on mlgM. These in vitro studies suggest that the use of the highest affi nity MoAbs for antireceptor immunotherapies that depend on receptor Cr oss-linking might, on occasion, be contraindicated. (C) 1998 by The Am erican Society of Hematology.