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) and CD7 (WT1) monoclonal antibody both conjugated to deglycosylated ricin A. In vitro efficacy data demonstrated that these IT act synergistically, resulting in an approximately 99% elimination of activated T cells at 10(-8 )mol/L (about 1.8 microg/mL). Because most natural killer (NK) cells are CD7(+), NK activity was inhibited as well. Apart from the killing mediated by ricin A, binding of SPV-T3a by itself impaired in vitro cytotoxic T-cell cytotoxicity. Flow cytometric analysis revealed that this was due to both modulation 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 been treated with 3 to 4 infusions of 2 or 4 mg/m(2) IT combination, administered 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 were restricted to limited edema, fever, and a modest rise of creatine kinase levels. One patient developed low-titer antibodies against ricin A. Infusions were associated with an immediate drop of circulating T cells, followed by a more gradual but continuing elimination of T/NK cells. One patient mounted an extensive CD8 T-cell response directly after treatment, not accompanied with aggravating GVHD. Two patients showed nearly complete remission of GVHD, despite unresponsiveness to the extensive pretreatment. These findings justify further investigation of the IT combination for treatment of diseases mediated by T cells. (Blood. 2000;95:3693-3701)
van Oosterhout
Y V
YV
Department of Hematology, University Nijmegen, Nijmegen, The Netherlands. y.vanoosterhout@chl.azn.nl
van Emst
L
L
Schattenberg
A V
AV
Tax
W J
WJ
Ruiter
D J
DJ
Spits
H
H
Nagengast
F M
FM
Masereeuw
R
R
Evers
S
S
de Witte
T
T
Preijers
F W
FW
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D019011:Antigens, CD7 / Q000276:immunology; D004359:Drug Therapy, Combination; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008875:Middle Aged; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology; D012276:Ricin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000911:Antibodies, Monoclonal; D019011:Antigens, CD7; D000922:Immunotoxins; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D012276:Ricin