Blood, Vol. 95 No. 12 (June 15), 2000:
pp. 3693-3701
A combination of anti-CD3 and anti-CD7 ricin A-immunotoxins
for the in vivo treatment of acute graft versus host disease
Ypke V. J. M. van Oosterhout,
Liesbeth van Emst,
Anton V. M. B. Schattenberg,
Wil J. M. Tax,
Dirk
J. Ruiter,
Hergen Spits,
Fokke M. Nagengast,
Roos Masereeuw,
Sabine Evers,
Theo de Witte, and
Frank W. M. B. Preijers
From the Departments of Hematology, Nephrology, Pathology,
Gastroenterology, and Pharmacology and Toxicology, University Nijmegen,
Nijmegen, The Netherlands; Department of Immunology, Dutch Cancer
Institute, Amsterdam, The Netherlands.
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 µg/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/m2 IT combination, administered intravenously
at 48-hour intervals. The T1/2 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.
