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Blood, Vol. 95 No. 12 (June 15), 2000:
pp. 3909-3914
Ki-4(scFv)-ETA', a new recombinant anti-CD30 immunotoxin
with highly specific cytotoxic activity against disseminated Hodgkin
tumors in SCID mice
Stefan Barth,
Michael Huhn,
Bärbel Matthey,
Samir Tawadros,
Roland Schnell,
Timo Schinköthe,
Volker Diehl, and
Andreas Engert
From the Medizinische Klinik I der Universität zu Koeln,
Cologne, Germany.
The human lymphocyte activation marker CD30 is highly overexpressed
on Hodgkin/Reed-Sternberg cells and represents an ideal target for
selective immunotherapy. We used the murine anti-CD30 hybridoma Ki-4 to
construct a new recombinant immunotoxin (rIT) for possible clinical use
in patients with CD30+ lymphoma. Hybridoma V genes were
polymerase chain reaction-amplified, assembled, cloned, and expressed
as a mini-library for display on filamentous phage. Functional Ki-4
scFv obtained by selection of binding phage on the CD30-expressing
Hodgkin lymphoma cell line L540cy was inserted into the bacterial
expression vector pBM1.1 and fused to a deletion mutant of
Pseudomonas exotoxin A (ETA'). Periplasmically expressed
Ki-4(scFv)-ETA' demonstrated specific activity against a variety
of CD30+ lymphoma cells as assessed by different in vitro
assays. To evaluate in vivo antitumor activity, severe combined
immunodeficient mice challenged with human lymphoma cell lines were
treated with the immunotoxin. The blood distribution time
t1/2 of Ki-4(scFv)-ETA' was 19 minutes,
and its serum elimination time t1/2 was 193 minutes. A single intravenous injection of 40 µg rIT 1 day after
tumor inoculation rendered 90% of the mice tumor free, extending the
mean survival time to more than 200 days compared with 38.1 days in the
phosphate-buffered saline control group (P < .001). This
new rIT is a promising candidate for further clinical evaluation in
patients with Hodgkin lymphoma or other CD30+ malignancies.
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