CD8 T-CELL ACTIVATION AFTER INTRAVENOUS ADMINISTRATION OF CD3XCD19 BISPECIFIC ANTIBODY IN PATIENTS WITH NON-HODGKIN-LYMPHOMA

A bispecific antibody directed to T and B cells (CD3 x CD19 bsAb) was daily infused intravenously in escalating doses from 10 mu g up to 5 mg in three patients with chemotherapy-resistant non-Hodgkin lymphoma; in this way we aimed to activate T cells to kill the malignant B cells. Only limited toxicity was observed, consisting of moderate fever preceded by chills or shivers and mild thrombocytopenia. No human anti(mouse Ig) antibodies were found. Pharmacokinetics showed a t(1/2) of 10.5 h with peak levels of 200-300 ng/ml after infusion of 2.5 mg bsAb. bsAb in serum was functionally active in vitro. After bsAb infusion a rise in serum tumour necrosis factor a was observed, accompanied by an increase in soluble CD8 and to some extent in soluble interleukin-2 receptor (IL-2R), but not in interferon gamma, IL-4 or soluble CD4. No evidence was found for monocyte activation (no increases in IL-6, IL-8 or IL-1 beta in serum). No gross changes in histology or number of IL-2R(+), CD4(+) or CD8(+) cells were found in the lymph nodes after therapy, but one patient showed activated CD8(+) T cells within the tumour nodules. In conclusion, after intravenously administered CD3 x CD19 bsAb only moderate toxicity was found, probably due to CD8(+) T cell activation and cytokine release, without CD4(+) T cell activation.