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Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 1157-1165
Molecular modification of a recombinant anti-CD3 -directed
immunotoxin by inducing terminal cysteine bridging enhances
anti-GVHD efficacy and reduces organ toxicity in a lethal murine
model
Daniel A. Vallera,
David W. Kuroki,
Angela Panoskaltsis-Mortari,
Donald J. Buchsbaum,
Buck E. Rogers, and
Bruce R. Blazar
From the Departments of Therapeutic Radiology, Section on
Experimental Cancer Immunology and Pediatrics, Division of Bone Marrow
Transplantation. University of Minnesota Cancer Center, Minneapolis,
MN, and Department of Radiation Oncology, University of Alabama at
Birmingham, Birmingham, AL.
Immunotoxin (IT) therapy shows potential for selectively eliminating
GVHD-causing T cells in vivo, but the field has been hampered by
toxicity. Previously, we showed that a genetically engineered IT
consisting of a single-chain protein, including the anti-CD3sFv spliced
to a portion of diphtheria-toxin (DT390) has anti-GVHD
effects, but pronounced organ toxicity common to this class of agent. A
recombinant DT390 anti-CD3sFv protein previously shown to have anti-GVHD activity was modified to reduce its
filtration into kidney by genetically inserting a cysteine residue
downstream of the sFv moiety at the c-terminus of the protein. This
modification produced an intermolecular disulfide bridge, resulting in
a bivalent, rather than a monovalent IT, termed SS2, that selectively
inhibited T-cell proliferation in vitro. Although monomer and SS2 were
similar in in vitro activity, SS2 had a superior therapeutic
index in vivo with at least 8-fold more being tolerated with
reduced kidney toxicity. Most importantly, in a lethal model of
GVHD, 40 µg SS2 given for 1 day, protected 100% of the mice from
lethal GVHD for 3 months, whereas the maximum tolerated dose (MTD) of
monomer protected only 33%. To our knowledge, this is the first
time disulfide bonded ITs have been created in this way and this simple
molecular modification may address several problems in the IT field
because it (1) markedly increased efficacy curing mice of GVHD after a single daily treatment, (2) markedly decreased organ toxicity, (3)
increased the tolerated dosage, and (4) created a therapeutic window
where none existed before.
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