Chimaeric Lym-1 monoclonal antibody-mediated cytolysis by neutrophils fromG-CSF-treated patients: stimulation by GM-CSF and role of Fc gamma-receptors

Chimaeric Lym-1 (chLym-1) is a monoclonal antibody generated by fusing the variable region genes of murine Lym-1 to human gamma1 and kappa constant re gions. Owing to its selectivity and avidity for human malignant B cells, it is an attractive candidate for developing Immune-interventions in B-lympho mas. In the attempt to identify rational bases for optimizing potential chL ym-1 related therapeutic approaches, we studied the ability of this ch-mAb to trigger neutrophil-mediated Raji cell cytolysis in cooperation with two neutrophil-related cytokines, G-CSF and GM-CSF ChLym-1 triggered low levels of cytolysis by normal neutrophils but induced consistent cytolysis in neu trophils from individuals treated with G-CSF When exposed to GM-CSF, neutro phils from subjects treated with G-CSF became potent effectors, also leadin g to 75% lysis. By using mAbs specific for distinct Fc gamma Rs, normal neu trophils were inhibited by mAb IV.3, suggesting the intervention of Fc gamm a RII, constitutively expressed on the cells. On the other hand, neutrophil s from patients treated with G-CSF were inhibited by mAb IV.3 plus mAb 197, a finding consistent with a cooperative intervention of FC gamma RII and G -CSF-induced Fc gamma RI. The anti-Fc gamma RIII mAb 3G8 promoted significa nt enhancement of the neutrophil cytolytic efficiency. Therefore, neutrophi l Fc gamma RIII behaves as a down-regulator of the cytolytic potential. The present findings suggest new attempts to develop mAb-based and G-CSF/GM-CS F combined immune-interventions in B lymphomas. (C) 2001 Cancer Research Ca mpaign.