A combination of anti-CD3 and anti-CD7 ricin A-immunotoxins for the in vivo treatment of acute graft versus host disease

This study evaluated the anti-graft versus host disease (GVHD) potential of a combination of immunotoxins (IT), consisting of a murine CD3 (SPV-T3a) a nd CD7 (WT1) monoclonal antibody both conjugated to deglycosylated ricin A. In vitro efficacy data demonstrated that these IT act synergistically, res ulting in an approximately 99% elimination of activated T cells at 10(-8) m ol/L. (about 1.8 mu g/mL), Because most natural killer (NK) cells are CD7(), NK activity was inhibited as well. Apart from the killing mediated by ri cin A, binding of SPV-T3a by itself impaired in vitro cytotoxic T cell cyto toxicity. Flow cytometric analysis revealed that this was due to both modul ation of the CD3/T-cell receptor complex and activation-induced cell death. These results warranted evaluation of the IT combination in patients with refractory acute GVHD in an ongoing pilot study. So far, 4 patients have be en treated with 3 to 4 infusions of 2 or 4 mg/m(2) IT combination, administ ered intravenously at 48-hour intervals. The T-1/2 was 6.7 hours, and peak serum levels ranged from 258 to 3210 ng/mL, Drug-associated side effects we re restricted to limited edema, fever, and a modest rise of creatine kinase levels. One patient developed low-titer antibodies against ricin A. Infusi ons were associated with an immediate drop of circulating T cells, followed by a more gradual but continuing elimination of T/NK cells. One patient mo unted an extensive CD8 T-cell response directly after treatment, not accomp anied with aggravating GVHD. Two patients showed nearly complete remission of GVHD, despite unresponsiveness to the extensive pretreatment, These find ings justify further investigation of the IT combination for treatment of d iseases mediated by T cells. (C) 2000 by The American Society of Hematology .